Elsevier

Redox Biology

Volume 25, July 2019, 101047
Redox Biology

Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress

https://doi.org/10.1016/j.redox.2018.11.005Get rights and content
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Abstract

Endoplasmic reticulum (ER) is a dynamic organelle orchestrating the folding and post-translational maturation of almost all membrane proteins and most secreted proteins. These proteins synthesized in the ER, need to form disulfide bridge to acquire specific three-dimensional structures for function. The formation of disulfide bridge is mediated via protein disulfide isomerase (PDI) family and other oxidoreductases, which contribute to reactive oxygen species (ROS) generation and consumption in the ER. Therefore, redox regulation of ER is delicate and sensitive to perturbation. Deregulation in ER homeostasis, usually called ER stress, can provoke unfolded protein response (UPR) pathways with an aim to initially restore homeostasis by activating genes involved in protein folding and antioxidative machinery. Over time, however, activated UPR involves a variety of cellular signaling pathways which determine the state and fate of cell in large part (like autophagy, apoptosis, ferroptosis, inflammation, senescence, stemness, and cell cycle, etc.). This review will describe the regulation of UPR from the redox perspective in controlling the cell survival or death, emphasizing the redox modifications of UPR sensors/transducers in the ER.

Abbreviations

APX
Ascorbate peroxidase
ATF4
Activating Transcription Factor 4
ATF6α
activating transcription factor 6α
ASK1
apoptosis signal-regulating kinase 1
CHOP
CAAT/enhancer binding protein (C/EBP) homologous protein
CRAC
Ca2+ release-activated Ca2+
ER
endoplasmic reticulum
eIF2α
eukaryotic translation initiation factor 2α
ERAD
ER-associated degradation
ERO1
ER oxidoreductin-1
GADD34
DNA damage gene 34
GPx7/8
glutathione peroxidase 7/8
GSH
reduced glutathione
GSSG
oxidized glutathione
GSTP
Glutathione S-Transferase P
IP3
inositol-1,4,5-trisphosphate
IP3R
inositol-1,4,5-trisphosphate receptor
IRE1α
inositol-requiring protein 1α
JNK
c-Jun NH2-terminal kinase
MAM
mitochondrial-associated membranes
NOX
NADPH oxidase
NRF2
nuclear factor erythroid 2-related factor 2
OPF
Oxidative protein folding
p-AKT
phosphorylated protein kinase B
PDI
protein disulfide isomerase
p-ERK
phosphorylated extracellular signal-regulated kinase
PERK
protein kinase RNA-like ER kinase
PRDX4
peroxiredoxin 4
QSOX
quiescin sulfhydryl oxidase
RIDD
regulated IRE1-dependent decay
ROS
reactive oxygen species
S1P
site-1 protease
S2P
site-2 protease
SERCA
sarcoplasmic/endoplasmic reticulum Ca2+-ATPases
SOCs
store operated Ca2+ channels
STIM1
stromal interaction molecule 1
TRAF2
TNF receptor-associated factor 2
TXNIP
thioredoxin interacting protein
UPR
unfolded protein response
VKOR
Vitamin K epoxide reductase
Vps34
vacuolar protein sorting 34
XBP1
X-box binding protein 1

Keywords

Redox regulation
ER stress
UPR
Cell fate

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1

These authors contribute equally to this work.