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Maintaining PeroxisomePopulations: A Story of Division and Inheritance

Andrei Fagarasanu, Monica Fagarasanu,and Richard A. Rachubinski

Department of Cell Biology, University of Alberta, Edmonton, Alberta T6G 2H7,

Canada; email: [email protected], [email protected],[email protected]

Annu. Rev. Cell Dev. Biol. 2007. 23:321–44

The Annual Review of Cell and Developmental Biology is online at http://cellbio.annualreviews.org

This article’s doi:10.1146/annurev.cellbio.23.090506.123456

Copyright c 2007 by Annual Reviews. All rights reserved

1081-0706/07/1110-0321$20.00

Key Words

yeast, organelle, dynamin, cell cycle, myosin, actin

Abstract

Eukaryotic cells divide their metabolic labor between functionally

distinct, membrane-enveloped organelles, each precisely tailored

for a specific set of biochemical reactions. Peroxisomes are ubiqui-

tous, endoplasmic reticulum–derived organelles that perform requi-

site biochemical functions intimately connected to lipid metabolism.

Upon cell division, cells have to strictly control peroxisome divi-sion and inheritance to maintain an appropriate number of peroxi-

somes in each cell. Peroxisome division follows a specific sequence

of events that include peroxisome elongation, membrane constric-

tion, and peroxisome fission. Pex11 proteins mediate the elongation

step of peroxisome division, whereas dynamin-related proteins ex-

ecute the final fission. The mechanisms responsible for peroxisome

membrane constriction are poorly understood. Molecular players

involved in peroxisome inheritance are just beginning to be elu-

cidated. Inp1p and Inp2p are two recently identified peroxisomal

proteins that perform antagonistic functions in regulating peroxi-

some inheritance in budding yeast. Inp1p promotes the retention

of peroxisomes in mother cells and buds by attaching peroxisomes

to as-yet-unidentified cortical structures. Inp2p is implicated in themotility of peroxisomes by linking them to the Myo2p motor, which

then propels their movement along actin cables. The functions of

Inp1p and Inp2p are cell cycle regulated and coordinated to ensure

a fair distribution of peroxisomes at cytokinesis.

321



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Contents

INTRODUCTION .. . . . . . . . . . . . . . . . 322

The Importance of MaintainingPeroxisome Populations . . . . . . . 322

PEROXISOME DIVISION. . . . . . . . . 325

Introduction to Peroxisome

Division . . . . . . . . . . . . . . . . . . . . . . 325

Elongation of Peroxisomes: The

Role of Pex11 Proteins . . . . . . . . 325

Constriction of the Peroxisomal

M e m b r a n e . . . . . . . . . . . . . . . . . . . . 3 2 7

Fission of Peroxisomes:

Involvement of

Dynamin-Related Proteins. . . . . 327

Other Proteins that Regulate the

Size and Number of Peroxisomes . . . . . . . . . . . . . . . . . . 329

PEROXISOME INHERITANCE . . . 329

Introduction to Peroxisome

Inheritance in Budding Yeast . . . 329

Retention of Peroxisomes: The

Role of Inp1p . . . . . . . . . . . . . . . . . 330

Transport of Peroxisomes: The

Role of Inp2p . . . . . . . . . . . . . . . . . 332

Coordination Between Peroxisome

Retention and Transport:

Interplay Between Inp1p and

Inp2p . . . . . . . . . . . . . . . . . . . . . . . . . 336

Inheritance of Peroxisomes in

Other Cell Types. . . . . . . . . . . . . . 337

CONCLUDING REMARKS . . . . . . . 338

INTRODUCTION

The Importance of Maintaining Peroxisome Populations

Compartmentalization of different metabolic

pathways into discrete membrane-bounded

compartments,or organelles, is a defining fea-

ture ofeukaryotic cells.By virtueof thisspatial

compartmentalization, eukaryotic cells areable to create interdependent, yet different,

microenvironments that separate potentially

competing biochemical reactions, thereby in-

creasing the overall efficiency of metabolic

activities.

Peroxisomes are single-membrane-

bounded organelles found in almost all

eukaryotic cells. Peroxisomes harbor a wide

spectrum of metabolic activities that vary among different species, developmental

stages, and cell types (Purdue & Lazarow

2001, Schrader & Fahimi 2006). Two widely

distributed and conserved functions of

peroxisomes are fatty-acid β-oxidation and

hydrogen peroxide (H2O2) metabolism.

Other metabolic pathways in peroxisomes

function in the α-oxidation of specific fatty

acids; the catabolism of purines, polyamines,

prostaglandins, and eicosanoids; and the

biosynthesis of plasmalogens and sterols.

Peroxisomes have also been implicated in

the metabolism of oxygen free radicals andnitric oxide. They are also involved in intra-

and intercellular signaling (Masters 1996,

Titorenko & Rachubinski 2004).

Given this array of peroxisomal functions,

it is not at all surprising that peroxisomes

are, under various conditions, indispens-

able organelles. Peroxisome-defective yeast

mutants fail to grow on various nutrients

that require peroxisomal enzymes for their

metabolism. These nutrients are diverse and

vary with yeast species, further underscoring

the versatility of peroxisomalfunctionsamong

different organisms. Peroxisomes are also es-sential for normal human development and

physiology, as demonstratedby the lethality of

the peroxisome biogenesis disorders, in which

peroxisomes fail to assemble correctly.

To preserve the advantages of having

peroxisomes, eukaryotic cells have evolved

molecular mechanisms that ensure the main-

tenance of the peroxisome population during

cell proliferation. Analyzing these mecha-

nisms requires a brief discussion of peroxi-

some formation.

For the past two decades, the prevail-

ing view of peroxisome formation has beenthat peroxisomes form by the growth and di-

vision of preexisting peroxisomes; i.e., they

seed their own growth (Lazarow & Fujiki

1985, Purdue & Lazarow 2001). This model

placed peroxisomes, like mitochondria and

322 Fagarasanu· Fagarasanu · Rachubinski



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chloroplasts, into the category of autonomous

organelles that cannot be made de novo.

The propagation of an autonomous or-

ganelle entails a constant import of bothlipids and proteins to enable it to sustain

membrane growth while preventing dilu-

tion of its protein constituents. According

to the growth-and-division model, all per-

oxisomal proteins are posttranslationally ac-

quired, whereas the endoplasmic reticulum

(ER) is only a possible source of membrane

lipids.

However, this long-standing paradigm

for peroxisome biogenesis has recently been

challenged by multiple observations that

compellingly showed that peroxisomes can

also form de novo from the ER (Titorenko

ER: endoplasmic

reticulumPMP: peroxisomalmembrane protein

et al. 1997, Titorenko & Rachubinski 1998a,

Mullen et al. 1999, Geuze et al. 2003,

Hoepfner et al. 2005, Tam et al. 2005, Kim

et al.2006). It is now well established that sev-eral peroxisomal membrane proteins (PMPs)

are initially sorted to the ER. Once in the ER,

these PMPs are sequestered into discrete spe-

cialized regions of theER membrane andthen

incorporated into expanding vesicles (for a

review, see Titorenko & Mullen 2006). These

vesicles eventually bud from the ER, gener-

ating peroxisomal precursor vesicles. In most

cells, these preperoxisomes are deemed to be

small vesicles that mature into peroxisomes

through a sequence of steps that probably

requires homotypic membrane fusion as

well as protein import (Figure 1). Fusion of

Figure 1

A model for peroxisome biogenesis and division. Preperoxisomal vesicles originate in specializedcompartments of the endoplasmic reticulum (ER). Fusion of these preperoxisomes is probably requiredto form a mature, metabolically active peroxisome. A retrograde pathway can be envisioned for theretrieval of escaped ER proteins and recycling of the preperoxisome assembly machinery. The division of peroxisomes proceeds through three distinct steps: elongation of peroxisomes, membrane constriction,and final fission of peroxisomal tubules. Pex11 proteins are implicated in the elongation step of peroxisome division, whereas dynamin-related proteins (DRPs) catalyze the fission event. A modificationin membrane lipid composition probably underlies the membrane curvature necessary for membraneconstriction. Peroxisomes grow by fusion with preperoxisomal vesicles and through the direct import of matrix and membrane proteins.

www.annualreviews.org • Peroxisome Division and Inheritance 323



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ER-derived preperoxisomal vesicles has

already been shown to occur in the yeasts

Yarrowia lipolytica (Titorenko et al. 2000) and

Pichia pastoris (Faber et al. 1998).Collectively, these observations indicate

that peroxisomes represent an outgrowth of

the ER and thus constitute another branch

of the secretory pathway (Titorenko &

Rachubinski 1998b, Schekman 2005). There-

fore, we posit that the biogenesis of peroxi-

somes obeys the same principles that govern

vesicular transport in the classical ER secre-

tory system.To maintain organelle homeosta-

sis, the forward movement of cargo from the

ER to the peroxisomalendomembrane system

must be accompanied by a retrograde, vesicle-

mediated transport forthe retrieval of escapedER-resident proteins (Bonifacino & Glick

2004) (Figure 1). Moreover, such an ER-

destined retrograde vesicular flow may also

be required for the recycling of those PMPs

that orchestrate the first stages of peroxisome

membrane assembly at the ER (Mullen &

Trelease 2006, Titorenko & Mullen 2006). To

date, such peroxisome-to-ER vesicular trans-

port has been observed only in infected plant

cells (McCartney et al. 2005). It remains to

be established whether this type of reverse

protein-sorting pathway also exists in unin-

fected plant cells and in the cells of otherorganisms.

Even though peroxisomes originate in the

ER,many observations areconsistent with the

view that they also can grow and divide (for

a review, see Schrader 2006). It is tempting

to speculate that during their growth, mature

peroxisomesacquire their membrane lipidsby

fusion with the same ER-derived preperox-

isomal vesicles that could otherwise homo-

typically fuse to form a “new” peroxisome.

Such a scenario would also provide a way for

those PMPs that constitutively pass through

the ER to be incorporated into a grow-ing peroxisome so that their concentrations

within the peroxisomal membrane are main-

tained during multiple rounds of peroxisomal

growthand division. Forexample,the integral

PMP Pex3p of the yeast Saccharomyces cere-

visiae reaches preexisting,mature peroxisomes

after initially sampling the ER membrane

(Hoepfner et al. 2005). Fusion of preper-

oxisomal vesicles with mature peroxisomesmay occur in plant cells (Mullen & Trelease

2006).

With this current view of peroxisomes as

organelles that canarise from the ER, but also

possess the ability to undergo growth and di-

vision, we can better understand the strate-

gies employed by cells to maintain peroxi-

some number during cell proliferation. Upon

cell division, cells have to double the num-

ber of their peroxisomes and distribute them

equitably between the two resulting cells.

How do cells achieve duplication of their per-

oxisome number in a cell-cycle-dependentmanner? The number of peroxisomes in a

cell is regulated through several processes

that can be conceptually divided as follows

(Figure 1):

1. De novo formationof peroxisomes from

the ER.

2. Peroxisome division, definedas thepro-

cess leading to the final scission of the

peroxisomal membrane and the forma-

tion of at least two peroxisomes.

3. Fusion of peroxisomal structures. In

contrast to other organelles like mito-chondria, there is no direct evidence

that mature peroxisomes can fuse with

each other. However, we have already

mentioned the fusion events that prob-

ably take place within the peroxiso-

mal endomembrane system. Preperoxi-

somal vesicles can fuse either with one

another to form “new” mature per-

oxisomes, thereby contributing to the

de novo formation of peroxisomes, or

with preexisting mature peroxisomes,

thereby contributing to the growth of

such peroxisomes. Consequently, thefate of preperoxisomal vesicles, which

may be influenced by species and en-

vironmental conditions (Mullen et al.

2001), has an important effect on per-

oxisome size and number in a cell.




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4. Pexophagy, which represents the spe-

cific degradation of peroxisomes. This

process occurs when cells are re-

leased from environmental conditionsin which peroxisomes proliferate. It

does not play a role in regulating per-

oxisome number during cell division.

Even though the molecular mechanisms

underlying each of these processes have be-

come ever more clearly defined, little is known

abouttheir relative contributions to maintain-

ing peroxisome homeostasis. It is well estab-

lished that peroxisomes divide during the cell

cycle independently of extracellular stimuli

to maintain their number in a growing cell

population (Titorenko & Rachubinski 2001). An important question is whether the dou-

bling of the number of peroxisomes during

cell division is due solely to the fission of pre-

existing peroxisomes or is also the result of

the synthesis of new peroxisomes. A recent

study (Kim et al. 2006) showed that both pro-

cesses, the division of peroxisomes and the

production of new ones, account for the for-

mation of peroxisomes in constitutively divid-

ing mammalian cells. Why would cells man-

ufacture peroxisomes anew when the fission

of preexisting peroxisomes should be suffi-

cient for preserving their number upon celldivision? The continuous de novo formation

of peroxisomes maintains the peroxisomal en-

domembrane system as a heterogeneous mul-

ticompartment in which individual peroxiso-

mal compartments are at different stages of

maturation. Peroxisomes at different stages of

maturation probably have distinct properties

that are needed for different functions in the

cell, including peroxisome partitioning (see

also the Peroxisome Inheritance section, be-

low). Therefore, it may be important not only

to preserve a constant number of peroxisomes

per cell but also to maintain the proportionbetween different populations of peroxisomes

within a cell. This article reviews recent find-

ings on the molecular mechanisms used by

eukaryotic cells to divide and partition their

peroxisomes.

PEROXISOME DIVISION

Introduction to Peroxisome Division

Peroxisomedivision must be coordinatedwiththe cell cycle to maintain the number of per-

oxisomes in each cell. However, peroxisomes

have the ability to proliferate, i.e., to increase

in number and/or size, in response to ex-

ternal stimuli that induce peroxisome-housed

enzymes. Probably the same set of proteins

choreographs peroxisome division, regardless

of whether it is cell cycle dependent or linked

to peroxisome proliferation (Yan et al. 2005).

The exact contribution of the ER to the

cell-cycle-related duplication of peroxisomes

and peroxisome proliferation remains to be

established. Multiple observations point to the exis-

tence of a tight coordination between perox-

isome maturation and division. In Y. lipolytica

and Hansenula polymorpha, peroxisomal vesi-

cles can undergo division only after they have

matured through the import of matrix pro-

teins, whereas in Candida boidinii , peroxisome

division precedes growth. However, in mam-

malian cells, both mature and immature per-

oxisomes have the ability to divide (Thoms &

Erdmann 2005).

Morphological observation shows that

peroxisome division proceeds through at leastthree partially overlapping steps: the elon-

gation of peroxisomes, the constriction of

the peroxisomal membrane, and the fission

of peroxisomes. Pex11 proteins are impli-

cated in the elongation step of peroxisome

division, whereas dynamin-related proteins

(DRPs) catalyze the final fission event. Little

is known about how the various components

of the peroxisome division machinery coor-

dinate their activities with events of the cell

cycle.

Elongation of Peroxisomes: The Role of Pex11 Proteins

Pex11p was the first protein to be im-

plicated in peroxisome division (Erdmann

& Blobel 1995, Marshall et al. 1995). In




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Saccharomyces cerevisiae, Pex11p-deficient cells

exhibited fewer, but considerably larger, per-

oxisomes as compared with the peroxisomes

of wild-type cells (Erdmann & Blobel 1995).Conversely, the overexpression of the PEX11

geneledtoanincreaseinthenumberofperox-

isomes. A striking feature of cells overproduc-

ing Pex11p was the appearance of elongated

peroxisomal structures. This distinctive phe-

notype implicated Pex11p in the tubulation

step of peroxisome division (Marshall et al.

1995, Yan et al. 2005) (Figure 1). Two ad-

ditional S. cerevisiae proteins, Pex25p (Smith

et al. 2002) and Pex27p (Rottensteiner et al.

2003, Tam et al. 2003), that share weak amino

acid sequence similarity to Pex11p have re-

cently been identified. Pex25p andPex27pareinvolved in peroxisome division and appear

to have functions partially redundant to that

of Pex11p. Pex11p, Pex25p, and Pex27p thus

form a protein family of low homology, the

Pex11 protein family, involved in the division

of peroxisomes.

Pex11p, Pex25p, and Pex27p are all pe-

ripheral PMPs, even though some contro-

versy still exists in the case of Pex11p. In-

dividual or pairwise deletions of proteins

belonging to the Pex11 protein family re-

sult in fewer and larger peroxisomes. Pex11

proteins, in addition to promoting perox-isome division, are required for the ef-

ficiency of transport processes across the

peroxisomal membrane. A lack of Pex11p im-

pairs the metabolic exchange of intermedi-

ates of fatty-acid metabolism across the per-

oxisomal membrane (van Roermund et al.

2000), whereas the pex11 / pex25 / pex27

triple-deletion strain of S. cerevisiae displays

a severe defect in the import of peroxi-

somal matrix proteins (Rottensteiner et al.

2003).

In mammals, three Pex11 isoforms, des-

ignated Pex11α, Pex11β, and Pex11 γ, havebeen identified. They are all integral PMPs

and have both their amino and carboxyl ter-

mini exposed to the cytosol. Some impor-

tant observations are worth mentioning. The

overproduction of Pex11β resulted in peroxi-

some tubulation, followed by an increase in

peroxisome number (Schrader et al. 1998).

However, in the absence of a functional DRP,

the overproduction of Pex11β resulted in per-oxisome hypertubulation alone, without an

increase in peroxisome number. This suggests

that Pex11 proteins cannot constrict or divide

peroxisomes themselves and most likely func-

tion upstream of DRPs by promoting peroxi-

somal membranetubulation (Koch et al.2003,

2004; Schrader 2006). Other eukaryotic cells

also contain multiple Pex11 isoforms: Cells

of the plant Arabidopsis thaliana contain five

Pex11 isoforms (Lingard & Trelease 2006),

whereas filamentous fungi have three Pex11

isoforms (Kiel et al. 2006).

Pex11 proteins interact with themselves,suggesting that they may form homodimers

or homo-oligomers (Marshall et al. 1996, Li

& Gould 2003, Rottensteiner et al. 2003,

Tam et al. 2003). In S. cerevisiae, homo-

oligomerization of Pex11pcorrelates with loss

of function, whereas a mutation that prevents

the self-association of Pex11p causes an in-

crease in peroxisome number (Marshall et al.

1996).

How do Pex11 proteins function? Some

hints about their mechanism of action come

from analysis of the structures of Pex11 pro-

teins from yeast. A region shared by Pex11pfamily members shows extensive amino acid

sequence similarity to the ligand-binding do-

mains of nuclear hormone receptors (Barnett

et al. 2000), especiallywith theligand-binding

domains of the peroxisome proliferator–

activated receptors, which bind fatty acids.

This observation may point to a role for

Pex11 proteins in phospholipid binding and

probably in peroxisome membrane modifica-

tion and may explain the multiple roles of

Pex11 proteins in peroxisome biology. It is

tempting to speculate that the membrane-

modifying activity of Pex11 proteins is re-sponsible for the tubulation of peroxisomes.

The same membrane-modifying properties

may also underlie the role of Pex11 proteins

in differenttransportprocesses across theper-

oxisomal membrane.




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Constriction of the Peroxisomal Membrane

Dynamins constitute a superfamily of large

GTPases that carry out a broad range of functions within the cell and are implicated

mainly in vesicle-scission reactions. On the

basis of the presence of specific domains

within their protein structure, dynamins

have been subdivided into classical dynamins

and DRPs (Praefcke & McMahon 2004).

Dynamin and DRPs are known for their abil-

ity to induce membrane curvature, which re-

sults in both the constriction and scission

of membranes (Praefcke & McMahon 2004,

McMahon & Gallop 2005). However, many

times, membranes are constricted by other

factors first, and then dynamins are recruitedto execute thefinal fission reaction. Forexam-

ple, in endocytosis, dynamin promotes mem-

brane scission only after clathrin and other

coat proteins have constricted the neck of

an endocytic vesicle (Osteryoung & Nunnari

2003).

Mammalian or yeast cells deficient in

peroxisomal DRPs display elongated perox-

isomes with segmented morphology, resem-

bling beads on a string (Hoepfner et al. 2001,

Kochetal.2003)(Figure1). Therefore,with-

out DRPs, peroxisomes are able to constrict

but are unable to divide. This suggests that

DRPs act late in the process of peroxisome

division, after the peroxisomal membrane has

been constricted through still poorly under-

stood mechanisms (Yan et al. 2005). Thus,

peroxisome constriction and peroxisome scis-

sion are distinct processes that require dis-

tinct sets of molecular components (Schrader

2006). Thinning of the peroxisomal tubule is

probably required for the DRP ring to be ef-

ficiently assembled around and promote the

scission of the peroxisome. The molecular

mechanisms mediating the constriction of theperoxisomal membrane are largely unknown.

Studies of Y. lipolytica have revealed an

interesting mechanism that controls mem-

brane constriction from inside peroxisomes.

Yl Pex16p is an intraperoxisomal peripheral

PMP that negatively regulates peroxisome

division (Eitzen et al. 1997, Guo et al.

2003). Yl Pex16pfunctions byinhibiting a lipid

biosynthetic pathway that leads to the for-mation of diacylglycerol, a potent inducer of

membrane curvature. The import of various

matrixproteins during the maturation process

of peroxisomes gradually displaces the per-

oxisomal enzyme acyl-CoA oxidase from the

matrix to the membrane, where this enzyme

interacts with and inhibits Yl Pex16p (Gregg

et al. 2006). As a result, the negative influ-

ence of Yl Pex16p on peroxisome division is

released by its interaction with acyl-CoA ox-

idase only in mature peroxisomes (Guo et al.

2003). This results in the local accumulation

of the cone-shaped diacylglycerol in the outerleaflet of the lipid bilayer, causing membrane

curvature and constriction. Yl Vps1p, a DRP,

is then recruited to the cytosolic face of the

membrane to execute the final fission of the

peroxisomal membrane (Gregg et al. 2006).

This mechanism explains why only mature

peroxisomes undergo division in Y. lipolytica.

It remains to be established whether the con-

striction of peroxisomal membranes in other

yeastspecies andmammaliancellsis alsoregu-

lated by components acting from the lumenal

side of peroxisomes. However, the molecular

players involved are expected to be different.S. cerevisiae does not have a Pex16p homolog,

butthe mammalian Pex16 protein has a role in

peroxisome biogenesis at the level of the ER

rather than in peroxisome division (Honsho

et al. 1998).

Fission of Peroxisomes: Involvement of Dynamin-Related Proteins

Dynamins and DRPs probably function as

mechanochemical enzymes that use GTPase-

dependent conformational changes to drivefission directly rather than through the re-

cruitment of downstream effectors (Praefcke

& McMahon 2004). Growing evidence sup-

ports the view that DRPs are essential for the

fission of peroxisomes in all cell types.




ANRV324-CB23-13 ARI 7 June 2007 15:12

Pleckstrin

homology (PH)domains: proteinsequences of approximately 100 amino acids inlength that bind aspecial class of lipidscalledphosphoinositides

Involvement of a DRP in peroxisome

fission was first observed in S. cerevisiae

(Hoepfner et al. 2001). The S. cerevisiae

genome encodes three DRPs (Dnm1p, Mgm1p, andVps1p)but no classical dynamin.

Of these DRPs, only Vps1p was found to be

required for peroxisome division. The num-

ber of peroxisomes in cells lacking Vps1p is

drastically reduced. Most cells lacking Vps1p

contain only one or two giant peroxisomes,

whichoftenappear as elongatedtubular struc-

tures. Ultrastructural analysis revealed that

these peroxisomes display constrictions and

appear like beads on a string (Hoepfner et al.

2001), showing that, in the absence of Vps1p,

peroxisomes still retain the ability to con-

strict their membranes. A partial colocaliza-tion of Vps1p with peroxisomes was detected.

Vps1p is required for peroxisome fission un-

der both peroxisome-inducing and noninduc-

ing conditions (Hoepfner et al. 2001, Li &

Gould 2003). Interestingly, Dnm1p, which

normally mediates mitochondrial fission, is

also required for peroxisome fission, espe-

cially under peroxisome-inducing conditions

(Kuravi et al. 2006). Evidence for this con-

clusion comes from the observation that the

deletion of the DNM1 gene in cells already

lacking Vps1p further decreases the number

of peroxisomes and causes virtually all cellsto contain a single, enlarged peroxisome. In-

terestingly, the giant peroxisomes observed

in vps1 and vps1 /dnm1mutants undergo

constitutivedivision and thenare correctly ap-

portioned between mother and daughter cells

(Hoepfner et al. 2001, Kuravi et al. 2006).

This observation suggests that neither Vps1p

nor Dnm1p plays a direct role in peroxi-

some distribution and inheritance. Further-

more, this finding points to the existence of

a dynamin-independent mode of peroxisome

division. Pulling forces exerted by the Myo2p

motor on the one hand, and retention mecha-nisms on the other hand, may act on the same

giant peroxisome, eventually tearing it apart

(Kuravi et al. 2006, van der Zand et al. 2006).

It remains tobe established if such a dynamin-

independent peroxisome fission also occurs in

wild-type cells,irrespective of mechanism (see

the Peroxisome Inheritance section, below).

Recently, investigators discovered the

DRP DLP1/Drp1 to be essential for peroxi-some division in mammalian cells (Koch et al.

2003, 2004; Li & Gould 2003; Tanaka et al.

2006).KnockdownofDLP1/Drp1bysiRNA-

mediated silencing ledto a reductionin perox-

isome number and an accumulation of elon-

gated peroxisomes. As already described for

yeast vps1 cells, these tubular peroxisomes

have a beads-on-a-strong segmented appear-

ance (Koch et al. 2004; Schrader 2006). Fur-

thermore, the overexpression of dominant-

negative mutants of DLP1/Drp1 exerted

similar effects on peroxisome morphology

(Koch et al. 2003, 2004; Li & Gould 2003). Very interestingly, DLP1/Drp1 is involved in

both peroxisome and mitochondrial fission in

mammalian cells (Schrader 2006).

DLP1/Drp1 physically associates with

peroxisomes. DLP1/Drp1 aligns in spots

along elongated peroxisomes (Koch et al.

2003). The peroxisomal localization of

DLP1/Drp1 is more readily detected upon

the overexpression of Pex11β (Koch et al.

2003, Li & Gould 2003) or when per-

oxisome proliferation is induced by treat-

ment with bezafibrate (Koch et al. 2003).

How are DRPs recruited to the peroxisomalmembrane? Classical dynamins associate with

membranes, using their pleckstrin homology

(PH) domains, which bind membrane lipids.

However, because DRPs lack PH domains,

other factors must recruit DRPs to the mem-

brane of their target organelles. Moreover,

these factors must be limiting because the

overexpression of wild-type DRPs does not

result in peroxisome (or mitochondrial) pro-

liferation (Koch et al. 2004). Fis1 is a candi-

date to be such an adaptor for DRPs in mam-

malian cells. Fis1, a DLP1-interacting protein

previously implicated in the process of mito-chondrial fission, was recently shown to func-

tion in peroxisome fission as well. Fis1 is an

integral membrane protein of both peroxi-

somes and mitochondria. Intriguingly, unlike

DLP1/Drp1, which concentrates at discrete




ANRV324-CB23-13 ARI 7 June 2007 15:12

sites of constriction on mitochondria and per-

oxisomes, Fis1 is uniformly distributed along

the membranes of these organelles. Knock-

down of Fis1 protein levels by siRNA resultsin the formation of elongated peroxisomes

and mitochondria, a phenotype resembling

the one observed in DLP1/Drp1-deficient

cells. It is noteworthy that the oversynthesis

of Fis1 causes an accumulation of numerous

minute peroxisomes and promotes mitochon-

drial fragmentation. These effects, which re-

quire a functionalDLP1/Drp1to occur (Koch

et al. 2005), show that Fis1 is a limiting factor

in the process of peroxisome and mitochon-

drial division. S. cerevisiae Fis1p interacts with

Dnm1p to promote mitochondrial division.

However, like Dnm1p, Fis1p also plays a rolein peroxisome division, especially under in-

duction conditions (Kuravi et al. 2006). It re-

mains to be established what proteins underlie

the association of Vps1p with peroxisomes in

S. cerevisiae.

The requirement for DRPs in peroxisome

fission has also been demonstrated in plants.

Mano et al. (2004) showed that DRP3A pro-

motesboth peroxisomeand mitochondrial fis-

sion in A. thaliana. Collectively, the aforemen-

tioned findings suggest that DRPs in various

organisms catalyze the last stage of peroxi-

some division by pinching off small peroxi-somes from already constricted tubules.

Other Proteins that Regulate theSize and Number of Peroxisomes

In addition to proteins belonging to thePex11

family and DRPs, several other peroxisomal

proteinsthataffectthesizeandnumberofper-

oxisomes have been discovered in the yeast S.

cerevisiae. Pex28p and Pex29p are two highly

homologous PMPs with redundant functions

(Vizeacoumar et al. 2003). Single or dou-

ble deletions of PEX28 / PEX29 genes resultin clusters of peroxisomes that often exhibit

thickened membranes between adjacent per-

oxisomes. This finding suggests that Pex28p

and Pex29p may be involved in the separa-

tion of peroxisomes after peroxisome divi-

Actin: a globular

protein thatpolymerizes in ahelical manner toform actin filaments(also calledmicrofilaments). In

yeast, long bundlesof actin filamentsthat span the wholecell are called actincables

sion (Vizeacoumar et al. 2003). Thus, these

two peroxins play a role in distributing per-

oxisomes within cells. However, lack of ei-

ther Pex28p or Pex29p does not disrupt thedistribution of peroxisomes at cell division,

and therefore neither peroxin is required for

peroxisome inheritance (A. Fagarasanu, M.

Fagarasanu, R.A. Rachubinski, unpublished

observations).

The PMPs Pex30p, Pex31p, and Pex32p

form another family of homologous per-

oxins implicated in the regulation of per-

oxisome size and number in S. cerevisiae

(Vizeacoumar et al. 2004). Lack of Pex30p

leads to an increase in the number of per-

oxisomes, whereas loss of either Pex31p or

Pex32p results in enlarged peroxisomes. The pex30 / pex31 / pex32 triple-deletion mu-

tant strain exhibits a pronounced increase

in the number of peroxisomes per cell. The

molecular mechanisms by which these pro-

teins influence peroxisome size and number

have yet to be elucidated.

PEROXISOME INHERITANCE

Introduction to PeroxisomeInheritance in Budding Yeast

The distribution of organelles during cell division has to be accurately controlled to en-

sure their faithful inheritance by the two re-

sulting cells. The segregation of organelles

between cells requires both their movement

along cytoskeletal elements, driven by molec-

ular motors, and their retention at specific in-

tracellular locations. In most eukaryotic cells,

the long-range movements of organelles oc-

cur along microtubules, whereas actin-based

motility is favored for short-range displace-

ments. Tight coordination between these two

cytoskeletal systems is generally required for

the correct positioningof various intracellularcompartments.

Studies of S. cerevisiae have contributed

much to our understanding of how organelles

partition at cell division. In contrast to cells

that divide by median fission, the budding




ANRV324-CB23-13 ARI 7 June 2007 15:12

displayed chaotic movements instead of be-

ing static and cortically localized, and no per-

oxisome maintained a fixed cortical position

for a prolonged period of time. Eventually, allperoxisomes were transported to the daugh-

ter cell. These observations strongly suggest

a role for Inp1p in the retention of perox-

isomes at the cell periphery. Moreover, the

complete transfer of all peroxisomes to the

bud as a result of their lack of attachment to

cortical structuresfurther underscores the im-

portance of activeretention in attaining an eq-

uitable distribution of peroxisomes upon cell

division. Consistent with a role for Inp1p in

anchoring peroxisomes, the overproduction

of Inp1p caused all peroxisomes in themother

cell to maintain static positions at the cell cor-

tex, which prevented their normal delivery todaughter cells. Interestingly, when Inp1p was

overproduced, it localized to the cell cortex

in addition to, as usual, peroxisomes. This

indicates that Inp1p has an intrinsic affinity

for structures lining the cell periphery and

probably represents the link between peroxi-

somes and an as-yet-unidentified cortical an-

chor (Fagarasanu et al. 2005) (Figure 2).

In addition to its role in anchoring per-

oxisomes in mother cells, Inp1p is probably

– + – +

Peroxisome

Cortical anchor

Inp1p

Inp2p

Myo2p

Actin

Formins

Figure 2

Proposed roles for Inp1p and Inp2p in peroxisome inheritance. Inp1p attaches peroxisomes to corticalanchors in the mother cell. Newly synthesized Inp2p is loaded onto a subset of peroxisomes and recruitsthe Myo2p motor to the peroxisomal membrane. The pulling force exerted by Inp2p-Myo2p transportcomplexes eventually dislodges peroxisomes from their fixed cortical positions. Myo2p carries attachedperoxisomes along polarized actin cables into the bud. In the bud, the Inp2p-Myo2p complexes areresponsible for initially localizing peroxisomes to the bud tip. This represents a first mechanism of retention for transferred peroxisomes. The regulated degradation of Inp2p results in the detachment of peroxisomes from the Myo2p motor, followed by their Inp1p-dependent anchoring at the bud cellcortex. The attachment of peroxisomes at the bud periphery represents a second mechanism of retentionfor peroxisomes delivered to the bud, but it also prepares the bud for the ensuing cell cycle, when it willhave to retain half of its peroxisomes.




ANRV324-CB23-13 ARI 7 June 2007 15:12

PEST sequences:

protein domains thatconsist of the aminoacids proline,glutamic acid, serine,and threonine andconferhypersensitivity toproteolyticdegradation onproteins

also involved in the retention of transferred

peroxisomes within buds. Cells lacking Inp1p

display a high frequency of peroxisomes that

aberrantly return to the mother cell. Inp1pmost likelyfunctionsin attaching peroxisomes

to cortical structures in the bud that are the

same as those in the mother cell. In wild-type

cells, peroxisomes transferred to the bud as-

sume static cortical positions after perform-

ing characteristic movements dependent on

the actomyosin system (see the next subsec-

tion, Transport of Peroxisomes: The Role of

Inp2p). This process is probably important

for preparing the bud for the next cell cy-

cle, when, as a mother cell, it will have to re-

tainsome of its peroxisomes (Fagarasanuet al.

2005, M. Fagarasanu et al. 2006) (Figure 2).

Inp1p levels vary during the cell cycle.

Inp1p protein levels fluctuate during the cell

cycle, peaking at the G2-M transition. This

probably reflects different requirements for

peroxisome retention during different stages

of the cell cycle. However, a significant

amount of Inp1p can be detected throughout

the cell cycle, indicative of a constant need

for Inp1p in the cell. This observation is con-

sistent with the need to immobilize peroxi-

somes at the mother cell and bud cortices dur-

ing all stages of the cell cycle, as observedin wild-type cells. Importantly, Inp1p may

contain a PEST sequence that may be in-

volved in its cell-cycle-dependentdegradation

(Fagarasanu et al. 2005).

A role for Inp1p in coordinating peroxi-

some inheritance and division. In addition

to having an abnormal distribution of perox-

isomes along the mother-bud axis, cells lack-

ing Inp1p also display fewer and larger per-

oxisomes as compared with wild-type cells.

This observation indicates an additional role

for Inp1p in regulating the size and num-ber of peroxisomes, possibly through its in-

volvement in peroxisome division. In sup-

port of this conclusion, Inp1p interacts with

Vps1p, Pex25p, and Pex30p (Fagarasanu et al.

2005), proteins previously implicated in per-

oxisome division (see Peroxisome Division

section, above). However, the two processes,

peroxisome retention and division, may be

intrinsically linked. The peroxisome divisionmachinery may function more effectively on

an anchored, immobilized peroxisome than

on a mobile one. It is also possible that reten-

tion mechanismswork with theMyo2p motor

together on a subset of peroxisomes and are

responsible for their division, as has been sug-

gested in the context of vps1 cells that con-

tain usually one or two highly enlarged per-

oxisomes (see Peroxisome Division section,

above). Cytoskeletal tracks and motor pro-

teins exert tensions on organelle membranes,

thus assisting in organelle fission (Schrader &

Fahimi 2006). To determine if the retentionand division of peroxisomes are inherently

linked or represent two different functions of

Inp1p, it will be important to determine if

these two processes are genetically dissectible

in the Inp1p molecule.

Transport of Peroxisomes: The Roleof Inp2p

The intracellular transport of organelles is

accomplished by both microtubule and mi-

crofilament (actin) networks in most eukary-

otic cells. Coordination between the twocytoskeletal systems is neededto correctly po-

sition the intracellular compartments in the

cell. In contrast to this dual cytoskeletal trans-

port system, the transport of most organelles

in S. cerevisiae is dependent exclusively on

actin filaments and, in most instances, is pow-

ered by class V myosins (Figure 3).

Myo2p: a versatilemolecular motor forthe

intracellular transport of organelles. Class

V myosins function as homodimers whose

amino-terminal heads associate with actin

and couple ATP hydrolysis to conformationalchanges that ultimately drive their movement

along actin filaments. Class V myosin motors

migrate along actin filaments, using a hand-

over-hand walking movement: Thetwo heads

alternateintheleadwitheachstep(Yildizetal.




ANRV324-CB23-13 ARI 7 June 2007 15:12

+

+

+PSV LG

Vacuole

–

–

–

Nucleus

mRNA

cER

Microtubule

Myo2p

Myo4p

Actin

Formins

Figure 3

Class V myosin–driven transport of organelles along actin cables in S. cerevisiae. Formins are localized atthe bud tip and bud neck, where they drive the assembly of polarized actin cables. Myo2p transportssecretory vesicles (SV), late compartments of the Golgi (LG), vacuolar elements (via the Vac8p-Vac17pcomplex), peroxisomes (P) (via Inp2p), and microtubule plus ends (via the Bim1p-Kar9p complex) intothe bud. Myo4p coordinates the transport of elements of the cortical endoplasmic reticulum (cER) withthat of specific mRNAs (via the She2p-She3p complex). Mitochondria probably do not engage a myosinmotor for their movement and instead use the propulsion generated by actin polymerization to advancetoward the bud (not depicted).

2003). Their carboxyl-terminal tail is repre-

sented by a globular domain specialized for

binding to cargo via adaptor receptor pro-

tein complexes (Provance et al. 2002, Wuetal. 2002, Ishikawa etal. 2003, A. Fagarasanu

et al. 2006). Class V myosins move proces-

sively along actin tracks and are able to take

hundreds of steps beforedissociating from the

underlying actin filament. This ensures the

efficient transport of their cargoes over mi-

crometer distances (Sellers & Veigel 2006).

Interestingly, these molecular motors advance

37 nm with each step, which corresponds ex-

actly to the helical periodicity of the actin fil-

ament (Mehta et al. 1999, Seabra & Coudrier

2004). This imposes a rectilinear trajectory of

cargoes, rather than a spiral one that wouldlead to an increased viscous drag, along the

actin filament axis (Sellers & Veigel 2006).

Collectively, these characteristics of class V

myosin motors make them ideally suited for

intracellular organelle trafficking and explain

Cortical ER:

consists of reticulartubular elements of the yeastendoplasmicreticulum that linethe cell periphery

why they are found ubiquitously in eukaryotic

cells.

The actin cables in S. cerevisiae are as-

sembled by a conserved class of proteinscalled formins. Formins function by hold-

ing onto the plus end of an actin filament

while incorporating newactin monomers into

the filament. As a result, formin-generated

actin cables elongate from their assembly site.

S. cerevisiae cells strategically anchor their

formins at the bud neck and tip, which re-

sults in the extension of a polarized array of

actincables deep into the mother cell. Class V

myosins capture various cargoes and use these

actincables as tracks to carry the attached car-

goes to the growing bud (Figures 2 and 3).

Budding yeast contains two class V myosins, Myo2pand Myo4p (for reviews, see Bretscher

2003, Pruyne et al. 2004) (Figure 3). Myo4p

is involved in the inheritance of cortical ER

(Estrada et al. 2003) and in the bud-destined

transport of at least 24 mRNAs (Shepard




ANRV324-CB23-13 ARI 7 June 2007 15:12

Vacuoles: essential

organelles in yeastinvolved in thestorage,detoxification, andturnover of proteins

et al. 2003). In contrast, Myo2p is an es-

sential protein that carries post-Golgi secre-

tory vesicles (Govindan et al. 1995), a pro-

cess indispensable for yeast growth. Myo2palso moves many other organelles for their

proper segregation, including late-Golgi el-

ements (Rossanese et al. 2001), a portion of

the vacuole (Hill et al. 1996), and peroxisomes

(Hoepfneret al. 2001). Myo2p is alsorequired

for proper orientation of the intranuclear mi-

totic spindle (Yin et al. 2000) and plays a role

in the retention of newly inherited mitochon-

dria (Boldogh et al. 2004).

Myo2p associates with various organelles

over distinct periods of the cell cycle, which

are both different and specific for each or-

ganelle type. This explains the establishmentof characteristic patterns of movement for

each organelle, even though the same molec-

ular motor carries different organelles. For

example, at cytokinesis, both late-Golgi ele-

ments andperoxisomes relocate to themother

bud-neck region, where Myo2p accumulates.

In contrast, vacuoles do not display Myo2p-

dependent movements at this stage of the cell

cycle, and no vacuolar structures are found

at the bud neck. Also, late compartments of

the Golgi follow Myo2p to the shmoo tips in

G1-arrested cells, in contrast to what

is observed for peroxisomes and vacuoles(Rossanese et al. 2001, Tang et al. 2003, A.

Fagarasanu et al. 2006).

How is the Myo2p tail able to discrim-

inate among its different cargoes in such

a cell-cycle-regulated manner? Interestingly,

Myo2p-dependent delivery of the vacuole and

secretory vesicles can be cleanly dissected in

theMyo2ptail(Schottetal.1999,Catlettetal.

2000). It has therefore been proposed that

each organelle has its own Myo2p-specific

receptor that binds to different regions in

the Myo2p tail. The identification of Vac17p,

which functions as the Myo2p receptor onthe vacuolar membrane (Ishikawa et al. 2003,

Tang et al. 2003), confirmed this hypothesis.

Importantly, Vac17p abundance during the

cell cycle parallels the motility and dynam-

ics of the vacuole, strongly suggesting that the

availability of organelle-specificreceptorsdic-

tates the timing of organelle movement. In-

spection of the crystal structure of the Myo2p

tailrevealedthattheregionsthatattachtovac-uoles and secretory vesicles are distant from

each other and simultaneously exposed on the

surface of the protein (Pashkova et al. 2006).

These observations further supported the idea

that organelle-specific receptors, rather than

Myo2p, are the main target for the regula-

tion of organelle motility (Weisman 2006). It

remains to be established if the Myo2p glob-

ular tail indeed possesses distinct and specific

regions devoted to binding eachorganelle, in-

cluding the peroxisome.

Inp2p is the peroxisome-specific receptor for Myo2p. Inp2p has been recently iden-

tified as the peroxisome-specific receptor for

Myo2p(A. Fagarasanu et al. 2006) (Figure 2).

Evidence forthis conclusioncomesfrom mul-

tiple observations, including the following.

(a) Inp2p is an integral PMP that interacts

directly with the globular tail of Myo2p.

(b) Peroxisomes in cells lacking Inp2p display

decreased velocities and fail to be delivered to

buds. As a result, mother cells retain the en-

tire peroxisome population. (c ) As is the case

for Vac17p and vacuole inheritance, Inp2p

levels oscillate with the cell cycle in a patternthat correlates with peroxisome dynamics.

(d ) The overproduction of Inp2p drives

the entire complement of peroxisomes out

of mother cells into buds, an event never

observed in wild-type cells. (e) Inp2p is

unequally distributed on different peroxi-

somes; it is preferentially enriched in those

peroxisomes delivered to the bud. ( f ) Inp2p

specifically affects peroxisome motility; we

know this because the segregation of other

organelles is unimpaired in cells lacking or

overproducing Inp2p.

Inp2p dynamics during the cell cycle. The

levels of both Inp2p and its corresponding

mRNA fluctuate during the cell cycle in a

pattern that correlates with the dynamics

of peroxisomes observed in wild-type cells.




ANRV324-CB23-13 ARI 7 June 2007 15:12

Inp2p becomes detectable during early bud-

ding, when peroxisome inheritance begins,

and its levels peak in medium-sized budded

cells, when most insertions of peroxisomesinto daughter cells occur. Given that Inp2p

functions as the peroxisome-specific receptor

for Myo2p, these observations suggest that

the regulated synthesis and turnover of Inp2p

coordinate peroxisomemotility with cell cycle

events.

Interestingly, the amounts of Inp2p in dif-

ferent peroxisomes vary widely; Inp2p lev-

els are highest in peroxisomes localized to

the bud. This suggests that Myo2p selec-

tively carries those peroxisomes that contain

high amounts of Inp2p, which results in a

highly polarized Inp2p gradient along themother-bud axis (A. Fagarasanu et al. 2006,

M. Fagarasanu et al. 2006). An interesting

phenomenon is that peroxisomes, once de-

livered to the bud, continue to accumulate

Inp2p, further contributing to the polariza-

tion of Inp2p along the division axis.

Recruitment of Inp2p by peroxisomes al-

ready transferred to daughter cells is likely

to increase their probability of remaining at-

tached to the Myo2p motor. This causes in-

herited peroxisomes to congregate at the bud

tip, where Myo2p accumulates and thereby

represents a mechanism for the retentionof peroxisomes in daughter cells. Myo2p

plays a similar role in the retention of other

organelles at the bud tip (Hill et al. 1996,

Rossanese et al. 2001, Boldogh et al. 2004).

Together, these observations indicate that the

Inp2p gradient across the cell division axis is

eventually established by the competency of a

subset of peroxisomes to recruit Inp2p contin-

uously, coupled with the selectivity of Myo2p

in carrying and then retaining only these

Inp2p-containing peroxisomes in the bud.

Inp2p is degraded later in the cell cycle,

resulting in the detachment of Myo2p fromtransferred peroxisomes. As a result, at cy-

tokinesis, only a few peroxisomes accompany

Myo2pto thebud-neckregion (A.Fagarasanu

et al. 2006, M. Fagarasanu et al. 2006). These

peroxisomes are the only ones that still con-

tain detectable levels of Inp2p at this stage of

thecell cycle. Importantly, the remaining per-

oxisomes withinthe budhave already assumed

static positions at the bud periphery. This ob-servation points to the existence of a tight co-

ordination between the factors promoting the

movement of peroxisomes and those regulat-

ing peroxisome retention(see next subsection,

Coordination Between PeroxisomeRetention

and Transport: Interplay Between Inp1p and

Inp2p).

A similar mechanism in which the regu-

lated disassembly of a transport complex dic-

tates the termination of organelle movement

was observed in the context of vacuole in-

heritance. Vacuole inheritance begins with

the formation of vesicular-tubular projectionsfrom the maternal vacuole, known as segre-

gation structures, that are rapidly carried into

the bud by the Myo2p-Vac17p-Vac8p com-

plex. Once in the bud, the transferred vac-

uolar structures first localize to the bud tip

and are retained there by Myo2p (Hill et al.

1996). The degradation of Vac17p later in

the cell cycle releases Myo2p from the vac-

uolar membrane, which results in the depo-

sition of the vacuole at the center of the bud

(Tang et al. 2003). The degradation of recep-

tors for molecular motors at cargo destina-

tions probably represents a general mecha-nism by which cells regulate the delivery of

cargoes to their correct intracellular locations

(Weisman 2006) (Figure 3).

If we assume that the Inp2p degradation

machinery is present in both the mother cell

and bud, its activation not only would cause

the release of bud-residing peroxisomes from

the grip of Myo2p but also would prevent

new recruitments of additional peroxisomes

from the mother cell. It would be important

to know whether the regulated degradation of

Inp2p, which terminates peroxisome inheri-

tance, is inherently initiated at a specific pointof the cell cycle or if it is triggered by cellular

surveillance mechanisms that monitor peroxi-

some partitioning (M.Fagarasanuet al. 2006).

Analysis of the possible mechanisms un-

derlying the preferential loading of Inp2p on




ANRV324-CB23-13 ARI 7 June 2007 15:12

only a subset of peroxisomes returns us to

the discussion of the origin of the peroxiso-

mal membrane. Many observations support

the view that peroxisomes constitute an ER-derived, heterogeneous, multicompartmental

organellar system in which individual preper-

oxisomal compartments undergo a stepwise,

time-ordered conversion to mature peroxi-

somes (Titorenko & Rachubinski 2001). Per-

oxisomes at distinct maturation stages differ

in their protein import competencies, which

can explain the association of Inp2p with only

a subset of peroxisomes. In this scenario, the

transfer of only the Inp2p-containing peroxi-

somes to the daughter cell would cause a dis-

turbance in the proportionality of the various

subpopulations of peroxisomes within cells.Regulating the ongoing de novo synthesis of

peroxisomes would tend to buffer this ten-

dencytoward disproportionality and helppre-

serve peroxisome homeostasis (see also Intro-

duction). An alternative explanation for the

presence of Inp2p on only a subset of peroxi-

somes would be that during peroxisome di-

vision, various membrane constituents may

segregate asymmetrically, conferring differ-

ent affinities for Inp2p on the resulting per-

oxisomes. Interestingly, to align their mitotic

spindles, S. cerevisiae cells use a similar mech-

anism that relates the age of structures totheir different segregation fates (Liakopoulos

et al.2003).Kar9p,the Myo2p receptor on cy-

toplasmic microtubules, is loaded onto only

the older of the spindle pole bodies, which

is inherited from the previous cell division.

This asymmetric loading of Kar9p ensures

that only one spindle pole is transmitted to

the bud, resulting in proper alignment of

the mitotic spindle with the cell division axis

(Figure 3).

Coordination Between PeroxisomeRetention and Transport: Interplay Between Inp1p and Inp2p

Collectively, the aforementioned observa-

tions indicate that Inp1p and Inp2p are two

key regulators of peroxisome inheritance

with apparently antagonistic functions. Inter-

estingly, the overproduction of one of the two

proteins negates the function of the other (M.

Fagarasanu et al. 2006). The Inp1p functionof retaining peroxisomes can be overcome

by the overproduction of Inp2p, a condition

that drives all peroxisomes into the bud (A.

Fagarasanu et al. 2006). Conversely, Inp2p’s

function in promoting the Myo2p-driven

transport of peroxisomes to daughter cells

is abolished by the overexpression of INP1,

which causes all peroxisomes to remain

immobile in the mother cell (Fagarasanu

et al. 2005). Furthermore, the effects caused

by the overexpression of either INP1 or INP2

are enhanced if the other gene is absent (A.

Fagarasanu et al. 2006, M. Fagarasanu et al.2006). Inp1p and Inp2p are unlikely to influ-

ence directly each other’s activities because

no interaction between these two proteins

has been detected (A. Fagarasanu et al. 2006).

We have proposed that a tug-of-war for

peroxisomes between the Inp1p-interacting

anchoring machinery and the Inp2p-Myo2p

transport complex may determine which

peroxisomes are recruited for transportation

to the bud (A. Fagarasanu et al. 2006, M.

Fagarasanu etal. 2006).In this scenario, Inp2p

is synthesized at a specific time in the cell

cycle and is then loaded onto peroxisomes. The increased levels of Inp2p on a subset of

peroxisomes result in the formation of Inp2p-

Myo2p transport complexes that can dislodge

these peroxisomes from their fixed cortical

positions (Figure 2). Cells have to fine-tune

and balance these molecular tugs-of-war to

allow for approximately only half of the per-

oxisomes to become mobile so that these cells

ultimately achieve a harmonious distribution

of their peroxisomes at cytokinesis.

A lack of Inp1p results in the complete

transfer of peroxisomes to the daughter cell

(Fagarasanu et al. 2005, M. Fagarasanu et al.2006). This suggests that all peroxisomes con-

tain Inp2p in sufficient amounts to promote

their Myo2p-driven movement in the absence

of an opposing force. However, in wild-type

cells, for approximately half the peroxisomes




ANRV324-CB23-13 ARI 7 June 2007 15:12

the regulation of Inp1p function counteracts

the tendency of peroxisomes to become mo-

bile (M. Fagarasanu et al. 2006).

Coordination between the functions of Inp1p and Inp2p is likely to occur in the bud

as well as in the mother cell. As soon as per-

oxisomes are delivered to the bud, they con-

gregate at the bud tip through the interaction

of Inp2p and Myo2p. Later in the cell cycle,

peroxisomes gradually start to relocate to the

bud cell cortex, where they gain fixed posi-

tions. Only a few peroxisomes follow Myo2p

back to the bud neck at cytokinesis. Most

peroxisomes are therefore transferred from

the grip of the Myo2p motor to the Inp1p-

interactingcortical anchors. Thisprocess mir-

rors the one that originally dislodged peroxi-somes from the mother cell cortex. We can

speculate that a tug-of-war between Inp1p

and Inp2p, similar to the one predicted for

the mother cell, determines whether a per-

oxisome becomes cortically anchored or re-

mains attached to Myo2p within the bud

(M. Fagarasanu et al. 2006). The regu-

lated turnover of Inp2p, which results in

the disassembly of Inp2p-Myo2p transport

complexes, probably swings the balance of

such molecular contests of strength toward

the establishment of Inp1p-cortex connec-

tions. Two observations are consistent withthis model. First, only those peroxisomes

that are carried by Myo2p back to the

bud neck at cytokinesis contain detectable

amounts of Inp2p. Second, bud-localized per-

oxisomes in both cells overproducing Inp2p

and cells lacking Inp1p often move en masse

to the mother bud-neck region at cytokinesis,

eluding the anchoring machinery altogether

(Fagarasanu et al. 2005, A. Fagarasanu et al.

2006) (Figure 2).

Inheritance of Peroxisomes in Other Cell Types

Eukaryotic cells that divide by fission, such

as mammalian cells, may ensure the accurate

partitioning of their organelles by adopting a

probabilistic strategy wherein the organelles

are dispersed more or less randomly in the cy-

toplasm. The cytokinetic machinery that di-

vides the cell into two equally sized daugh-

ter cells may also apportion the organellesmore or less equitably to the resultant cells.

In this scenario, the greater the copy num-

berof organelles in the mitotic cell cytoplasm,

the higher the accuracy of their inheritance

(Warren & Wickner 1996). However, multi-

plelines of evidence suggest that, even though

the distribution of several organelles in the

cytoplasm is apparently stochastic, eukary-

otic cells strictly regulate the movements and

positions of all their organelles. Mammalian

cells contain a large number of peroxisomes,

which, in contrast to other organelles such

as the Golgi complex, are uniformly dis-persed in thecytoplasm (Schraderet al. 2003).

Mammalianperoxisomes are very mobile,and

their motility depends on the microtubule cy-

toskeleton. Peroxisomes associate with mi-

crotubules both in vivo (Rapp et al. 1996;

Wiemer et al. 1997; Schrader et al. 1996,

2000;Huberetal.1999)andinvitro(Schrader

et al. 1996, 2000). Because peroxisomes dis-

play movements both toward and away from

the cell center, their motility is likely to be

propelled by members of both the dynein and

kinesin families (Schrader et al. 2003). Al-

though the involvement of dynein and its ac-tivator complex, dynactin, in the intracellu-

lar motility of mammalian peroxisomes has

been demonstrated (Schrader et al. 2000), ev-

idence implicating kinesins in this process

is circumstantial. The peroxisomal proteins

that recruit the translocation machineries to

the peroxisomal membrane have yet to be

elucidated.

Disruption of microtubule-based peroxi-

some motility in mammalian cells leads to

a loss of the uniform distribution of per-

oxisomes in the cytoplasm (Schrader et al.

2003). This suggests that a cell regulates thetransport of peroxisomes to disperse them,

which is important both for their proper

segregation upon cell division and for their

metabolic efficiency. It remains to be es-

tablished if the actin cytoskeleton plays any




ANRV324-CB23-13 ARI 7 June 2007 15:12

role in the motility of peroxisomes in mam-

malian cells, especially at the cell periph-

ery, as it does for other organelles. Recently,

Kural et al. (2005) showed that peroxisomemotility in Drosophila S2 cells was based

on microtubules and propelled by multiple

kinesins and dyneins that coordinate their

actions to increase the resulting velocity of

peroxisomes.

CONCLUDING REMARKS

The past two decades have witnessed re-

markable progress in our understanding of

peroxisome biology. Notably, a large array

of genes encoding proteins required for the

peroxisome biogenesis have been clonedand characterized, including those whose

mutations underlie Zellweger syndrome and

other members of the peroxisome biogenesis

disorders. Importantly, the debate on the

origin of peroxisomes has finally subsided

into an interesting marriage of the two seem-

ingly contradictory concepts of peroxisome

biogenesis: de novo formation of peroxisomes

from the ER and the growth and division of

preexisting peroxisomes.

However, the total inventory of proteins

implicated in peroxisome division and inheri-

tance is far from complete. Even less is known

about the molecular players that orchestratethe vesicular flow from the ER and through

the peroxisomal endomembrane system. The

challenge now is to identify and characterize

functionally theentire set of proteins involved

in peroxisome biogenesis, division, and inher-

itance. In addition, it is worthwhile to setaside

the view of these different processes as be-

ing independent and self-contained. Instead,

understanding how they are coordinately in-

tegrated will provide invaluable information

about the strategies used by cells to maintain

peroxisomes under varied and varying condi-

tions. A starting point to elucidate the relativecontributions of peroxisome de novo forma-

tion, division, and inheritance to peroxisome

homeostasis is to take advantage of new fluo-

rescent live-cell-imaging technologies such as

photo-chase assays (Kim et al. 2006), in dif-

ferent cell types and under different environ-

mental conditions. Defining the panoply of

peroxisome dynamics in real time will be an

exciting goal for cell biologists in the years to

come.

SUMMARY POINTS

1. Peroxisomes are endoplasmic reticulum–derived organelles involved in multiple

metabolic pathways. Cells divide and distribute their peroxisomes upon cell division

to ensure their equitable inheritance by the resultant daughter cells.

2. Peroxisome division proceeds through three partially overlapping steps: peroxisome

elongation, peroxisome constriction, and peroxisome fission.

3. Pex11 proteins are implicated in the elongation of peroxisomes.

4. Dynamin-related proteins execute the fission of already elongated peroxisomes.

5. The inheritance of organelles is strictly regulated and depends on both the transport

and retention of organelles at specific intracellular locations.6. In the yeast Saccharomyces cerevisiae, the peroxisomal membrane protein Inp1p acts

to anchor peroxisomes to cortical structures in the mother cell as well as in the bud.

Inp1p therefore acts to retain a specific subset of peroxisomes in the mother cell while

preventing the retrograde transport of peroxisomes already transmitted to the bud.




ANRV324-CB23-13 ARI 7 June 2007 15:12

7. The class V myosin Myo2p drives the movement of peroxisomes in S. cerevisiae

along actin cables. Inp2p is the peroxisome-specific receptor for Myo2p and thereby

links peroxisomes to the tranlocation machinery that propels their bud-directedmovement.

8. In mammals, peroxisome movement is dependent on the microtubule cytoskele-

ton. Cells use microtubule-based motors to disperse peroxisomes, a process im-

portant for both peroxisome inheritance and the increased metabolic efficiency of

peroxisomes.

FUTURE ISSUES

1. The nature of the complexes formed by the different families of peroxins involved in

the control of peroxisome size and number and the mechanism of their cross talk to

control peroxisome division need to be determined.2. The molecular mechanisms underlying peroxisome elongation, constriction, and fis-

sion need to be elucidated.

3. The nature of the structure(s) to which peroxisomes anchor in the mother cell and

bud should be determined.

4. The means by which Inp1p functions both in peroxisome division and peroxisome

inheritance requires definition.

5. Whether the Myo2p globular tail possesses distinct and specific regions devoted to

the binding of each organelle, including the peroxisome, needs to be established.

6. The molecular mechanism(s) of turnover of Inp1p and Inp2p during the cell cycle

should be discovered.

7. The molecular players and mechanisms underlying peroxisome inheritancein the cells of more complex eukaryotes, including humans, should be

defined.

DISCLOSURE STATEMENT

The authors are not aware of any biases that might be perceived as affecting the objectivity of

this review.

ACKNOWLEDGMENTS

We thank members of the Rachubinski laboratory for insightful discussion and valuable com-

ments on the manuscript. We apologize to those colleagues whose work was not cited owingto space constraints. Our work on peroxisome inheritance is supported by Grant 9208 from

the Canadian Institutes of Health Research. A.F. and M.F. are recipients of Studentships from

the Alberta Heritage Foundation for Medical Research. R.A.R. holds the Canada Research

Chair in Cell Biology and is an International Research Scholar of the Howard Hughes Medical

Institute.




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