Biomedical Engineering Reference
In-Depth Information
BiP
IRE1
α
IRE1
β
PERK
Golgi
ER lumen
BiP
BiP
Ca
2+
Ca
2+
α
β
7
3
4
H
O
pC-12
TRAF2
m-Calpain
S1P
S2P
TRAF2
IKK
ASK1
XBP1
NRF2
eIF2
α
H
α
α
·SREBP2
α
·XBP-1
3
4
C-12
O
α
β
Chaperones
Membrane
remodeling
ERAD
MKK4
MKK7
MKK3
MKK6
I
κ
B
ATF4
Membrane
remodeling
ERAD
Chaperones
Chaperones
Translation
attenuation
ERAD
Cell cycle arrest
NRF2·ATF4
CHOP
Acute phase
response
genes
NF-
κ
B
JNK
p38
I
κ
B
C-9
Inflammation
IRS
Bcl-2
TRB3
C-3
AKT
Glucose
metabolism
Glycogen synthesis
Lipid synthesis
Translation
Cytosol/nucleus
Antioxidant
response
Apoptosis
Apoptosis
Fig. 2. Principal signal transduction pathways in the mammalian UPR. Reprinted in modified form from Fig. 6 published
in Schröder (
1
), copyright 2007, Birkhäuser Basel, with kind permission of Springer Science and Business.
translation and transcription of genes encoding secretory proteins
(Fig.
2
). In addition, the UPR activates inflammatory and apop-
totic signaling pathways (Fig.
3
) and signaling pathways involved
in immune responses.
Folding stress signals are transduced across the ER membrane
by several transmembrane proteins, type 2 transmembrane tran-
scription factors such as ATF6a and ATF6b, the protein kinase
PERK, and the protein kinases-endoribonucleases IRE1a and
IRE1b. Two competing models for how these proteins sense
ER stress are discussed in the literature. In the competition
model, the ER stress sensors are kept in an inactive form through
interaction with ER luminal chaperones, especially the HSP70
class chaperone BiP/GRP78 (
3
). Accumulation of unfolded
proteins in the ER sequesters BiP away from the ER luminal
domains of the ER stress sensors, leading to their activation.
In IRE1 and PERK BiP release unmasks dimerization motifs,
in ATF6a sequences mediating transit of ATF6 to the Golgi
complex (
4, 5
). While widely accepted, this model cannot
explain several experimental observations. Most importantly,
yeast Ire1p deleted for all BiP binding sites was still activated
by ER stress, and remained inactive in the absence of ER stress
(
6
). Solution of the crystal structure of the core region of the
ER luminal domain of Ire1p revealed an MHC-like peptide-
binding pocket in an Ire1p dimer (
7
). Consequently, it was
proposed that direct interaction of the ER luminal domain
with unfolded proteins induces oligomerization of Ire1p. In in vitro
aggregation assays, this core region displayed chaperone activity,
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