Magazine R907

Quick guide

The unfoldedprotein response

Aditi Chawla and Maho Niwa

Where does the UPR function?Between the endoplasmicreticulum (ER) and the nucleus ofeukaryotic cells. All secretedproteins and proteins that reside insecretory compartmentstranslocate as nascent peptidechains into the ER, where they mayundergo folding, modification andassembly before assuming theirfunctional conformations. The ERmaintains a specialized oxidizingenvironment to aid chaperones andother components to promotedisulphide bonding, glycosylation,folding and assembly. The ER alsomediates protein quality control toensure that only properly foldedproteins exit the ER.

What is the UPR? UPR signalingis triggered when the protein-processing capacity of the ER isexceeded by the current demand.In yeast, it results in thetranscriptional upregulation ofmore than 300 genes encoding ERchaperones (e.g., BiP, calreticulin,calnexin), protein-folding enzymes(e.g., PDI, FKB2), regulators ofphospholipid metabolism, andproteins involved in degradingpermanently misfolded proteins.

How are unfolded proteins inthe ER lumen sensed by theUPR? In yeast, the only knownUPR sensor is IRE1, a type I ERtransmembrane receptorkinase/endoribonuclease. IRE1senses ER protein folding needsthrough its luminal domain. Prior toUPR activation, IRE1 is held in amonomeric conformation by BiP (amajor ER chaperone) bound to itsluminal domain. Rising levels ofunfolded proteins cause BiPdissociation, leading to IRE1oligomerization and kinaseactivation. Activated IRE1 thenfunctions as the site-specificendoribonuclease responsible forcleaving a unique intron from HAC1

mRNA (XBP1 mRNA in mammals).The resulting spliced form of HAC1mRNA (and XBP1) encodes apotent UPR-specific transcriptionfactor critical for upregulating UPRtarget genes.

How is ER stress sensed inhigher eukaryotes? In addition toIRE1, higher eukaryotes utilize twoadditional sensors, the ERtransmembrane kinase PERK andthe ER transmembranetranscription factor ATF6 (Figure 1).Both proteins are activated in amanner similar to IRE1 followingthe dissociation of BiP bound totheir ER luminal domains. In thecase of PERK, BiP dissociationpromotes phosphorylation of itssubstrate, the translation initiationfactor eIF2αα, at serine 51, resultingin inhibition of translation. In thecase of ATF6, BiP releasepromotes ATF6 translocation to theGolgi where an active transcriptionfactor fragment is produced andtranslocates to the nucleus.

What are the consequences ofactivating UPR? In addition totranscription of the UPR targetgenes and a decrease in proteintranslation, UPR activationproduces a transient cell-cyclearrest at G1/S in higher eukaryotes.From this resting point, cells mayadapt successfully to the impendingstress or commit to apoptosis.

What physiological eventstrigger UPR pathway activation?The best studied example of UPR

activation in a physiological eventis during the maturation of restingB cells into immunoglobulin-secreting plasma cells, a processin which IRE1-mediated splicing ofXBP1 mRNA has been shown to bea critical event. In addition, animportant role for UPR signaling inthe insulin-secreting pancreatic ββcells is suggested by a genetic linkbetween PERK and a certain typeof juvenile diabetes.

What remains to be discovered?Many things, such as the molecularevents leading to BiP dissociationfrom UPR sensors, the mechanismof UPR downregulation, and thepotential links between ER proteinload and levels of ER membranephospholipids.

Where can I find out more?Bertolotti, A., Zhang, Y., Hendershot,

L.M., Harding, H.P., and Ron, D.(2000). Dynamic interaction of BiPand ER stress transducers in theunfolded protein response. Nat. CellBiol. 2, 326–332.

Kaufman, R.J., Scheuner, D., Schroder,M., Shen, X., Lee, K., Liu, C.Y., andArnold, S.M. (2002). The unfoldedprotein response in nutrient sensingand differentiation. Nat. Rev. Mol.Cell Biol. 3, 411–421.

Patil, C., and Walter, P. (2001).Intracellular signaling from theendoplasmic reticulum to thenucleus: the unfolded proteinresponse in yeast and mammals.Curr. Opin. Cell Biol. 13, 349–356.

Division of Biological Sciences, Sectionof Molecular Biology, University ofCalifornia, San Diego, 9500 Gilman Drive,La Jolla, California 92093-0377, USA.

Figure 1. The UPR in higher eukaryotes. See text for details.

ER lumen

Cytosol

eIF2αP

XBP1 mRNA Transcriptionfactor

Cell cycle arrest and transcription activation

Survival Death

ATF6

Transcriptionfactor

Proteolyticcleavage

Decrease intranslation

IRE1

Kinase Endoribonuclease

PERK

Kinase

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