Download Unfolded Protein Response (UPR)

Isolation of yeast mutant which can not induce expression of BiP mRNA against
misfolded protein accumulation in the ER.
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Two suggested models for IRE1 (Inositol requring protein 1) function
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Identification of a molecule regulating by IRE1 protein
Basic leucine zipper (bZIP) transcription factor Hac1
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▶basic–leucine zipper transcription factor, Hac1p
▶Splicing replaces the C-terminal tail of Hac1p
and the tail has strong transcriptional activity.
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A schematic of the unfolded protein response in yeast.
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Looking for transcription factors which bind to BiP promoter
Nucleotide sequence of the 2140 to 219 region of the human GRP78 promoter.
List of ERSE-like sequences for the known vertebrate GRP
(Glucose regulated protein) promoters.
CCAAT-N9-CCACG
Locations and directions of ERSE-like sequences (closed arrowheads) in
the respective GRP promoters.
TATA box
ERSE-like seq
Isolation of transcription factors binding to BiP promoter
by yeast one-hybrid system
Isolation of two clones which encode XBP1 (X-box binding protein 1) and ATF6a
(activating transcription factor a) containing a bZIP motif
as a DNA-binding domain, separately.
ER stress-dependent size change of XBP1 during ER stress
Xbp1 mRNA Is spliced in response to ER Stress
IRE1-dependent splicing to XBP1 is a highly conserved event
from yeast to mammal.
It generates a strong transcription factor to regulate ER function.
The 2nd ER stress sensor
Protein translation and folding are coupled by an ER resident kinase
Nature. 1999 Jan 21;397(6716):271-4
Control of translation initiation by eIF2 complex
Met
GDP
GTP
eIF2•GTP
Met-tRNAi
eIF2B
Met
eIF2•GDP
g
eIF2•GTP•
b a
ternary complex
Met
AUG codon recognition
60S
AUG
eIF2•GTP•
40S
mRNA
43S•mRNA complex
Translation
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80S initiation complex
Control of translation initiation by eIF2a kinases
Global translation OFF
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Control of translation initiation by PERK during ER stress
Misfolded protein accumulation
Tg
Global translation OFF
signal transduction
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Unfolded Protein Response (UPR)
PERK
IRE1
ER Lumen
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UPR Signaling Responses
P
P
P
P
PERK
IRE1
unfolded
proteins
unfolded
proteins
ER Lumen
UPR Signaling Responses
Nucleus
ER Chaperone
XBP1s
XBP1u
Splicing
P
P
P
P
PERK
IRE1
unfolded
proteins
unfolded
proteins
ER Lumen
UPR Signaling Responses
Nucleus
ER Chaperone
XBP1s
XBP1u
eIF2a P
eIF2a
Splicing
P
Global translation
OFF
5’
5’
(GCN2, PKR, HRI)
P
P
P
PERK
IRE1
unfolded
proteins
unfolded
proteins
ER Lumen
How is the UPR sensed ?
How are the sensor proteins regulated?
Dynamic interaction of BiP and ER stress transducers
in the unfolded protein response (UPR)
Nat Cell Biol. 2000 Jun;2(6):326-32
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Unfolded Protein Response (UPR)
PERK
IRE1
BiP
BiP
ER Lumen
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Unfolded Protein Response (UPR)
Nucleus
ER Chaperone
XBP1s
XBP1u
eIF2a P
eIF2a
Splicing
P
(GCN2, PKR, HRI)
P
P
P
PERK
IRE1
unfolded
proteins
Global translation
OFF
5’
5’
BiP
ER Lumen
unfolded
proteins
Proteasome
ER-Associated Degradation
Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16113-8
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Isolation of transcription factors binding to BiP promoter
by yeast one-hybrid system
The 3rd ER stress sensor
Isolation of two clones which encode XBP1 (X-box binding protein 1) and ATF6a
(activating transcription factor a) containing a bZIP motif
as a DNA-binding domain, separately.
The 3rd ER stress sensors: ATF6a/b (activating transcription factor a/b)
Mammalian transcription factor ATF6 Is synthesized as a transmembrane Protein and
activated by proteolysis in response to Endoplasmic Reticulum stress
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Unfolded Protein Response (UPR)
Nucleus
ER Chaperone
XBP1s
XBP1u
eIF2a P
eIF2a
Splicing
P
(GCN2, PKR, HRI)
P
P
P
PERK
IRE1
unfolded
proteins
BiP
ER Lumen
ATF6
a/b
Global translation
OFF
5’
5’
Golgi
Processing
unfolded
proteins
Proteasome
ER-Associated Degradation
To be continued
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