CHMI 2227 - E.R. Gauthier, Ph.D. 1 CHMI 2227F Biochimie I Enzymes: - Régulation.
CHMI 4237 E Special topics in Biochemistry
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CHMI 4237 ECHMI 4237 E
Special topics in Special topics in BiochemistryBiochemistry
Eric R. Gauthier, Ph.D.Dept. Chemistry-Biochemistry
Laurentian University
Stress signaling
1CHMI 4237 E - Winter 2010
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Cell stressesCell stresses
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Chemicals
Radiation
Osmotic pressure
Nutrient
Heat
Viruses
Hypoxia
MechanicalOxidative
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Cellular responses to stressCellular responses to stress
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Cell cyclearrest
Death
Adaptation
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Cellular responses to stressCellular responses to stress
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Cell cyclearrest
Death
Adaptation
- Metabolic rewiring
- Differentiation
- Plasticity
- Motility
- Defense
- Aging
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Cellular responses to stressCellular responses to stress
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Stress Adaptation Example
Oxidative stress Metabolic rewiringIncrease in NAPH-producing pathways
Hypoxia DifferentiationIncrease in red blood cells
Increased exercise PlasticityChange in muscle fiber type
Wound Motility Wound closure
Foreign RNA Translation arrest Viral infection
Food shortage Lifespan increase Caloric restriction
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1. Response to nutrient starvation1. Response to nutrient starvation
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Food shortage
Cell cycleProtein synthesis
Alternative food sourceOR
Commit suicide
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1. Response to nutrient starvation1. Response to nutrient starvation Blocking ATP-vorous processes Blocking ATP-vorous processes
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http://8e.devbio.com/image.php?id=187
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http://8e.devbio.com/im
age.php?id=188
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http://8e.devbio.com/im
age.php?id=188
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eIF2 phosphorylation leads to eIF2 phosphorylation leads to translation arresttranslation arrest
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http://deverlab.nichd.nih.gov/graphics/fig3a.gif
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GCN2 – linking amino acid GCN2 – linking amino acid availability with translationavailability with translation
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http://deverlab.nichd.nih.gov/sub_rec.htm
The EMBO Journal Vol. 20 No. 6 pp. 1425-1438, 2001
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ATF4 translation is INCREASED ATF4 translation is INCREASED when eIF2 is phosphorylated…when eIF2 is phosphorylated…
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Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443
uORF = - upstream open reading frame (i.e. upstream of the ATF4 ORF)- uORF1 encodes for a 3-amino acid protein- uORF2 overlaps with the ATF4 ORF but is out of frame.
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ATF4 translation is limited when ATF4 translation is limited when amino acids are plentyfulamino acids are plentyful
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Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443
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ATF4 translation is limited when ATF4 translation is limited when amino acids are plentyfulamino acids are plentyful
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Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443
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ATF4 gene targetsATF4 gene targets
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Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443
TranscriptionInitiation machinery
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ATF4 gene targetsATF4 gene targets
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Tren
ds in
En
do
crino
log
y & M
etabo
lismV
olume 20, Issue 9, N
ovember 2009, P
ages 436-443
Gene Function
ASNS Amino acid synthesis
SNAT2CAT-1
Amino acid transporters
4EBP-1 Translation arrest
ATF3CHOP
Transcription factors
TRB3 AKT inhibitor
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GCN2/eIF2 and feeding behaviorGCN2/eIF2 and feeding behavior
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Mo
lecu
lar
Cel
l, V
ol.
18, 1
41–1
48, A
pri
l 15,
200
5
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mTOR: the art of sensing mTOR: the art of sensing nutrientsnutrients
mTOR:◦ Protein serine kinase◦ Same family as ATM
Inhibited by Rapamycin◦ Rapamycin: secreted by
Streptomyces hygroscopicus◦ From Rapa Nui (aka Easter Island)
Senses:◦ Glucose◦ Amino acids◦ Energy levels
Triggers: ◦ AKT activation◦ Translation◦ Proliferation
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HEAT repeats: protein interaction domainFAT domain: domain structure shared by FRAP, ATM and TRRAP
NA
TU
RE
RE
vIEW
S | M
olecu
lar cell Bio
log
y vOlU
ME
10 | MA
y 2009 | 307
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mTORC1: targeting translationmTORC1: targeting translation
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Oncogene (2006) 25, 6416–6422
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mTORC1: targeting translationmTORC1: targeting translation
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NATURE REvIEWS | Molecular cell Biology vOlUME 10 | MAy 2009 | 307
mTORC1
p70 S6K
S6 ribosomal
protein
eIF4B
↑ eIF4A helicaseactivity↑ translation
efficiency
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mTORC1: wide ranging effectsmTORC1: wide ranging effects
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http://www.cellsignal.com/reference/pathway/mTor.html
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PRAS40PRAS40
mTORC1 regulationmTORC1 regulation
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TSC 1/2: ◦ GTPase activating enzyme
targets Rheb◦ Mutated in patients with
Tuberous Sclerosis
Rheb: ◦ small G protein◦ In GTP-bound form: activates
mTOR
NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | DECEMBER 2005 | 989
mTOR
RaptorGL
AKTAKT
mTOR
RaptorGL
PRAS40PRAS40PO4
PRAS40◦ Binds mTORC and inhibits
it;◦ Dissociates form mTORC
upon phosphorylation by AKT
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mTORC1 regulationmTORC1 regulation
CHMI 4237 E - Winter 2010 23http://www.lsi.umich.edu/files/ken_research_fig1.jpg
NATURE REvIEWS | Molecular cell Biology vOlUME 10 | MAy 2009 | 307
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Glucose and mTORC1Glucose and mTORC1
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NATURE REvIEWS | Molecular cell Biology vOlUME 10 | MAy 2009 | 307
http://www.lsi.umich.edu/files/ken_research_fig1.jpg
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When glucose in plenty…When glucose in plenty…
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ATP
GLUCOSEGLUCOSE
Glycolysis
Acetyl-CoA
TCA
ATP
NADH
CO2
Citrate
Fatty acids
ETC
ATP
Energyreserves
Glycogen
ATP ADP
Cellular processes
ETC
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When glucose in scarce…When glucose in scarce…
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ATP
GLUCOSEGLUCOSE
Glycolysis
Acetyl-CoA
TCA
ATP
NADH
CO2
Citrate
Fatty acids
ETC
ATP
Energyreserves
Glycogen
Glutamine
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But, how are glucose levels But, how are glucose levels sensed?sensed?
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ATP ADP
ADP KinaseADP Kinase
ADPAMP
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But, how are glucose levels But, how are glucose levels sensed?sensed?
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ATP ADP
ADP KinaseADP Kinase
ADPAMP
AMPK
Adaptation
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AMPK and mTORC1AMPK and mTORC1
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http://www.cellbiol.net/ste/alpobesity4.php
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Other targets of AMPKOther targets of AMPK
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http
://w
ww
.cel
lsig
nal.c
om/r
efer
ence
/pat
hway
/AM
PK
.htm
l
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Other targets of AMPKOther targets of AMPK- carbohydrate metabolism- carbohydrate metabolism
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Other targets of AMPKOther targets of AMPK- lipid metabolism- lipid metabolism
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Other targets of AMPKOther targets of AMPK- cell cycle- cell cycle
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Other triggers of AMPKOther triggers of AMPK
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Other triggers of AMPKOther triggers of AMPK- adrenalin- adrenalin
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Adrenalin
http://www.cellbiol.net/ste/alpobesity4.php
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Other triggers of AMPKOther triggers of AMPK- adrenalin- adrenalin
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http://www.cellbiol.net/ste/alpobesity4.php
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Other triggers of AMPKOther triggers of AMPK- adrenalin- adrenalin
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http://www.cellbiol.net/ste/alpobesity4.php
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Oth
er
trig
gers
of
Oth
er
trig
gers
of
AM
PK
AM
PK
- In
su
lin
- In
su
lin
http://stke.sciencemag.org/content/sigtrans/vol2006/issue346/im
ages/large/3462006re7F
1.jpeg
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Amino acids and mTORAmino acids and mTOR
CHMI 4237 E - Winter 2010 39http://www.efdeportes.com/efd131/leucine-stimulates-mtor-01.jpg
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Amino acids and mTORAmino acids and mTOR
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677387/pdf/nihms103321.pdf
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Autophagy – cell cannibalismAutophagy – cell cannibalism
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nature cell biology volume 9 | number 10 | O CTOBER 2007 5 NOVEMBER 2004 VOL 306 SCIENCE
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Autophagy – cell cannibalismAutophagy – cell cannibalism
CHMI 4237 E - Winter 2010 42Biochem. J. (2005) 391, 191–202
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Autophagy: autophagosome Autophagy: autophagosome formationformation
Autophagosome
18
Atg9
9
Membrane transport?
1 13
1
Atg1/ULK1
13
Atg13
mTOR
Starvation
Vps34
Vps34
PI3P
PhagophoreNucleation
2
Atg2/18
Atg23/27
PhagophoreElongation
Atg16
Atg12 Atg5LC3-I
Atg10 GlyLC3-IIAtg4
Atg3
LC3-II
PtdE
Atg7
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LC3 – a marker of autophagyLC3 – a marker of autophagy
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http://www.cellsignal.com/products/4108.html
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Autophagy: fusion with lysosomeAutophagy: fusion with lysosome
Autophagosome
Lysosome
Atg22
Cathepsins
H+
H+
ADP+ Pi
ATP
Autolysosome
Aminoacids
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Autophagy - modulationAutophagy - modulation
Inhibitingautophagy
Lysosome
H+
H+
ADP+ Pi
ATP
Bafilomycin A
Chloroquine
Atg9
9
Lipid transport?
1 13
113
mTOR
Rapamycin
Increasing autophagy
PI3P
3-MA
Vps34
Beclin UVRAC
p150
Vps34
BeclinUVRAC
p150
Bcl2 Bcl2