The Role of ER Stress and Translation in Cell Death
Transcript of The Role of ER Stress and Translation in Cell Death
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Randal J. Kaufman, Ph.D.
Departments of Biological Chemistry & Internal MedicineInvestigator, Howard Hughes Medical Institute
University of Michigan Medical Center
Ann Arbor, MI
The Role of ER Stress and Translation in Cell Death
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Calcium storage and gated release
Oxidative protein folding
Quality control
ER-associated protein degradation
Core oligosaccharide biosynthesis
Lipid and sterol biosynthesis
The Endoplasmic Reticulum:
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Chinese hamster ovary cell
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Factor VIII Expression Induces ER Stress
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Activation of the Unfolded Protein Response
Calcium depletion thapsigargin, ionophore
Altered glycosylation tunicamycin, castanospermine
Nutrient deprivation (GRP) glucose, hypoxia
Reductive/oxidative stress DTT, homocysteine
Growth arrest / DNA damage (GADD) etoposide, UV
Protein expression wild-type / mutant / subunits
UPR
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Activation of the Unfolded Protein Response
Pathological conditions:
Viral infection, tumorigenesis, DNA damage, diabetes,
atherosclerosis, ischemic injury, conformational diseases
Physiological responses:
Glucose regulation of insulin production (β cells)
Response to a misfolded protein (hepatocytes)
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ER Lumen
Nucleus
ER Chaperone
The Unfolded Protein Response
ER-Associated Degradation
Proteasome
5’
Translation Attenuation
5’
TranscriptionalActivation
ERSE
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ER Lumen
Nucleus
ER Chaperone
The Unfolded Protein Response
ER-Associated Degradation
Proteasome
5’
Translation Attenuation
5’
TranscriptionalActivation
PERKIRE1
ATF6 / CREBH
ERSE
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ER Lumen
PERK
Nucleus
IRE1
ATF6 / CREBH
ER Chaperone
The Unfolded Protein Response
BIP
S1P/S2P Golgi
mRNA Splicing
XBP1uXBP1s
P P P P
ER-Associated Degradation
Proteasome
eIF2α eIF2α P
5’ ATF4 Specific
5’ General
mRNATranslation
5’
5’
Anti-ROS AA metabolismApoptosis (CHOP)
ATF4
ERSE
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ER Lumen
unfoldedproteins
unfoldedproteins
ER-Associated Degradation
PERK
Splicing
XBP1uXBP1s
Nucleus
IRE1
ATF6 / CREBH Golgi
Processing
5’
eIF2α eIF2α P
5’
5’5’ ATF4 Specific
General
BiP
Proteasome
ER Chaperone
UPR Signaling Responses
P P P P
B lymphocytes /Hepatocytes /Acinar cells Pancreatic β cells
Inflammation
mRNATranslation
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ER
Mitochondria
Nucleus
ER Stress-Induced Apoptosis
Casp 9
Cyt-c
Casp 3
APAF1
BH3 only
Apoptosis
Ca+2
Casp 12
pCasp 12
Calpain
IRE1
TRAF2
JNK-P
ER stress
PERK
Chop
Bcl-2
ATF-6
ATF-4
Gadd34
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ER perturbation by mild stress
NT 25 ng/ml Tm overnight 25 ng/ml Tm 2 weeks
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All stress pathways are activated during
mild stress
ATF6α
PERK
IRE1α
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Differential outcomes for UPR pathways during
persistent stress
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Selective instability of mRNAs in the PERK-
CHOP axis
Cells pretreated to induce UPR and ActD added to block transcription
hours0 4
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Selective instability of proteins in the PERK-CHOP axis
Cells pretreated to induce UPR and CHX added to block translation
BiPGrp94p58IPK
ATF4CHOPGADD34
Long (>8h) half-life
Short (<4h) half-life
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5’
UPR-induced Alterations in Gene Expression
adaptive pro-apoptotic
ATF4
eIF2α CHOPPPP
PERK
XBP1PP Chaperones, ERADIRE1
ATF6 Chaperones (BiP)
GADD34
BCL2
T1/2
T1/2
T1/2 T1/2
T1/2
Rutkowski et al. PLOS Biol. (In Press)
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eIF2α Kinase
Translation Initiation Response to External Stimuli
PERK HRI
PKRGCN2
eIF2α - PeIF2α
High rate of AUGcodon recognition
Low rate of AUGcodon recognition
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eIF2α Kinase
Translation Initiation Response to External Stimuli
PERK
Hemin DeficiencyArsenite
HRI
dsRNA
Amino Acid Starvation
ER Stress
PKR
TNFα
GCN2
Growth Factor Depletion
ER Ca++
Depletion
Virus Infection
eIF2α - PeIF2α
High rate of AUGcodon recognition
Low rate of AUGcodon recognition
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eIF2α Kinase
Translation Initiation Response to External Stimuli
PERK
Hemin DeficiencyArsenite
HRI
dsRNA
Amino Acid Starvation
ER Stress
PKR
TNFα
GCN2
Growth Factor Depletion
ER Ca++
Depletion
Virus Infection
eIF2α - PeIF2α
High rate of AUGcodon recognition
Low rate of AUGcodon recognition
Ser51Ala knock-in
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1 2 3 4
S/S A/A- + - + Thapsigargin
eIF2α phosphorylation is required for translation attenuation upon ER stress
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S/S
A/A
eIF2α A/A mice die within 24 hr after birth
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Glucose Rescue of eIF2α A/A Mouse
A/A
S/S
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Insulin Glucagon
S/S A/A
A/A islets have reduced β-cells and insulin content
Scheuner et al. 2001 Mol. Cell 7: 1165
Insulin
Glucagon
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Translational control is required to prevent ERdistension/stress in pancreatic β cells
A/A
S/S
2 µM 0.5 µM
*
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Wolcott-Rallison Syndrome
Rare autosomal recessive disorder
Diabetes mellitus in early infancy
Multiple epiphyseal dysplasia/osteoporosis
Growth retardation
Due to mutations in PERK/PEK
Delépine et al. 2000 Nat. Gen. 25: 406
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+
Partial loss of UPR
Diabetes
?
Does the UPR play a role in the etiology of type II diabetes?
DIET ENVIRONMENTAL STRESS GENETIC FACTORS
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DIET ENVIRONMENTAL STRESS GENETIC FACTORS
High-Fat or db/db
+
Partial loss of UPR (eIF2α S/A)
Diabetes
?
Does the UPR play a role in the etiology of type II diabetes?
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15 WksTime (wks)
S/A HF
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1520
25
30
35
40
45
50
55
Bo
dy
Wei
gh
t (g
)
HF
S/A
LF
Heterozygous eIF2α S/A mice become obese upon high-fat diet
S/S
S/S HF
S/A HF
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S/A
0 40 80 120
Time (min)
0
200
400
600
800
1000
1200
0 50 100 150 200 250
Time (min)
Blo
od
Glu
cose
(mg
/dL
)
S/S
0
0.5
1
1.5
2
Insu
lin (
ng
/ml)
0 40 80 120
Time (min)
Heterozygous eIF2α S/A mice are glucose intolerantwith impaired insulin secretion in vivo
S/S S/A
Scheuner et al. 2005 Nat. Med. 11: 757
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500 nm
High-fat diet induces ER stress in beta cells of eIF2α S/A mice
HF S/S HF S/A LF S/A
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Genotype: S/S S/A S/S S/A
LF HF
BiP
Proinsulin
Diet:
Antibody: α BiP
Increased Association of Proinsulin with BiPin HF-Fed S/A Mice
α PC2
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Genotype: S/S S/A S/S S/A
LF HF
BiP
Proinsulin
Diet:
Increased Association of Proinsulin with BiPin HF-Fed S/A Mice
HFLF
Insulin
Antibody: α BiP α Insulin
α PC2
S/S S/A S/S S/A
Scheuner et al. 2005 Nat. Med. 11: 757
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The UPR is essential for beta cell compensation
Fatty acid
Insulin resistance
Insulin secretion / transcription / translation
Increased ER load
UPR activation
ER integrity preserved
(Beta cell compensation)
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The UPR is essential for beta cell compensation
Fatty acid
Insulin resistance
Insulin secretion / transcription / translation
Increased ER load
UPR activation
ER integrity preserved
(Beta cell compensation)
+ eIF2α S/A (Partial loss of UPR)
ER dilation/ER stress
Beta cell decompensation
Glucose intolerance
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The UPR is essential for beta cell compensation
Fatty acid
Insulin resistance
Insulin secretion / transcription / translation
Increased ER load
UPR activation
ER integrity preserved
(Beta cell compensation)
+ eIF2α S/A (Partial loss of UPR)
ER dilation/ER stress
Beta cell decompensation
Glucose intolerance
CHOP
Apoptosis
?
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CHOP deletion increases HF-induced obesity in eIF2αS/A mice
wk0
5
10
15
20
25
0 5 10 15
CHOP(wt)-eIF2α S/S
CHOP(wt)-eIF2α S/A
CHOP(KO)-eIF2α S/S
CHOP(KO)-eIF2α S/A
To
tal w
eig
ht
gai
n (
g)
CHOP(KO)-S/A
CHOP(WT)-S/A
wt-S/A vs ko-S/A ∗ P<0.05; ∗∗ P<0.01
∗∗ ∗
∗∗∗∗
∗ ∗
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5 wkHF diet
12 wk
17 wk 32 wk
Blo
od
glu
cose
leve
ls (
mg
/dL
)
Time post glucose injection (min)
CHOP deletion prevents HF diet-induced glucose intolerance in eIF2αS/A mice
0
200
400
600
800
1000
1200
0 40 80 120 0 40 80 120
0
200
400
600
800
1000
1200
0 40 80 120 0 40 80 120
CHOP(wt)-S/S
CHOP(wt)-S/A
CHOP(ko)-S/S
CHOP(ko)-S/A
wt-S/A vs ko-S/A∗ P<0.05∗∗ P<0.01 ∗∗∗ P<0.001
∗∗
∗
∗∗ ∗∗
∗∗∗∗
∗
∗
∗∗∗∗
∗∗∗
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CHOP deletion promotes islet hyperplasia in high fat eIF2αS/A mice
wt-S/S wt-S/A ko-S/S ko-S/A
400µm
100µm
50µm
Insulin Glucagon
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Chop+/+ S/S Chop-/- S/AChop+/+ S/A
CHOP deletion restores insulin granulesand secretion in HF-fed eIF2αS/A mice
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Chop+/+ S/S Chop-/- S/AChop+/+ S/A
CHOP deletion restores insulin granulesand secretion in HF-fed eIF2αS/A mice
02468
10
Insu
linse
cret
ion
(% c
onte
nt) 3mM glucose
15 min17mM glucose30 min
17mM glucose60 min
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Does expression of a malfolded protein induce the UPR, oxidative stress, and
apoptosis in vivo?
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Does expression of a malfolded protein induce the UPR, oxidative stress, and
apoptosis in vivo?
Clotting factor VIII inefficiently secreted due tomisfolding.
Does factor VIII expression activate the UPR and apoptosis in vivo?
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FVIII expression after hydrodynamic DNA injection
C1 C2B A3A1 A2
A1 A2 C1 C2A3B
A1 A2 C1 C2A3
FVIII
226/N6*
BDD
* Miao et al., 2004 Blood 103:3412
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0
500
1000
1500
2000
2500
3000
3500
Vect FVIII BDD 226/N6
mU
/ml A
ctiv
ity
Vector
FVIII
FVIII expression after hydrodynamic DNA injection
C1 C2B A3A1 A2
A1 A2 C1 C2A3B
A1 A2 C1 C2A3
FVIII
226/N6*
BDD
* Miao et al., 2004 Blood 103:3412
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Vect
FVIII
BDD
226/N6
FVIII Expression Induces Apoptosis in Mouse Liver
TUNEL Nomarski` KDEL Csp-12 Merge`
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Vect FVIII BDD 226/N6
Vect
FVIII
BDD
226/N6
0
20
40
60
80
100
DNAse Vect FVIII BDD 226/N6
% A
po
pto
sis
Chop-/-CHOP is required for FVIII induced apoptosis
DNAse
TUNEL Nomarski
Chop-/-
0
5
10
15
20
25
30
35
*
*
*
*p<0.05(n=5)
Chop+/+
% A
po
pto
sis
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p-JNK
JNK1
CHOP
p-eIF2α
BiP
Actin
Vect FVIII BDD 226/N6
FVIII Expression Induces ER Stress in Liver
Spliced XBP1mRNA
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ER
Mitochondria
Nucleus
ER Stress-Induced Oxidative Stress
IRE1
PERK
Chop
Bcl-2
ATF6
Gadd34
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ER
Mitochondria
Nucleus
ER Stress-Induced Oxidative Stress
IRE1
ER stress
PERK
Chop
Bcl-2
ATF6
Gadd34
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ER
Mitochondria
Nucleus
ER Stress-Induced Oxidative Stress
IRE1
ER stress
PERK
Chop
Bcl-2
ATF6
Gadd34
ROS
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ER
Mitochondria
Nucleus
ER Stress-Induced Apoptosis
BH3 only
Ca+2
IRE1
ER stress
PERK
Chop
Bcl-2
ATF6
Gadd34
ROS
ROS
TRAF2
JNK-P
Casp 12
Casp 9
Casp 3
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ER
Mitochondria
ER Stress-Induced Apoptosis
ER stress
BH3 only
Ca+2
ROS
ROS
IRE1
TRAF2
JNK-P
Casp 12
Casp 9
Casp 3Nucleus
PERK
Chop
Bcl-2
ATF6
Gadd34
ATF-4
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ACKNOWLEDGEMENTS
Kaufman Laboratory, U of M
Donalyn Scheuner
Benbo Song Kezhong Zhang Robert ClarkSung-hoon Back Kenji SakakiJyoti MalhotraTom RutkowskiMark RibickJun Wu
Past:Stacey ArnoldMartin Schroder Xiaohua ShenEdward McEwen Kyungho Lee Chuan Yin LiuWitoon Tirasophon
Ajith Wehlinda
Dept. of Pediatrics, U of MSteven PipeHonghi Miao
UM Transgenic Animal Core
Patrick Gillespie
Thom SandersLinda Samuelson
Joslin Diabetes Center
Ross Laybutt
Susan Bonner-Weir
Vrije Universiteit BrusselDiabetes Research Center
Daisy Flamez
Frans Schuit
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