TY - JOUR
T1 - PERK-dependent compartmentalization of ERAD and unfolded protein response machineries during ER stress
AU - Kondratyev, Maria
AU - Avezov, Edward
AU - Shenkman, Marina
AU - Groisman, Bella
AU - Lederkremer, Gerardo Z.
N1 - Funding Information:
We are grateful to O. Elroy-Stein, D. Ron, E. Wiertz, T. Rapoport, R. Kopito, K. Hirschberg, R. Ehrlich and T. Yoshimori for generously providing reagents. This work was supported by grants from the US–Israel Binational Science Foundation, from Bio-disc/BMBF and from German–Israeli projects (DIP).
PY - 2007/10/1
Y1 - 2007/10/1
N2 - Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the ER membrane kinases PERK and IRE1 leading to the unfolded protein response (UPR). We show here that UPR activation triggers PERK and IRE1 segregation from BiP and their sorting with misfolded proteins to the ER-derived quality control compartment (ERQC), a pericentriolar compartment that we had identified previously. PERK phosphorylates translation factor eIF2α, which then accumulates on the cytosolic side of the ERQC. Dominant negative PERK or eIF2α(S51A) mutants prevent the compartmentalization, whereas eIF2α(S51D) mutant, which mimics constitutive phosphorylation, promotes it. This suggests a feedback loop where eIF2α phosphorylation causes pericentriolar concentration at the ERQC, which in turn amplifies the UPR. ER-associated degradation (ERAD) is an UPR-dependent process; we also find that ERAD components (Sec61β, HRD1, p97/VCP, ubiquitin) are recruited to the ERQC, making it a likely site for retrotranslocation. In addition, we show that autophagy, suggested to play a role in elimination of aggregated proteins, is unrelated to protein accumulation in the ERQC.
AB - Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the ER membrane kinases PERK and IRE1 leading to the unfolded protein response (UPR). We show here that UPR activation triggers PERK and IRE1 segregation from BiP and their sorting with misfolded proteins to the ER-derived quality control compartment (ERQC), a pericentriolar compartment that we had identified previously. PERK phosphorylates translation factor eIF2α, which then accumulates on the cytosolic side of the ERQC. Dominant negative PERK or eIF2α(S51A) mutants prevent the compartmentalization, whereas eIF2α(S51D) mutant, which mimics constitutive phosphorylation, promotes it. This suggests a feedback loop where eIF2α phosphorylation causes pericentriolar concentration at the ERQC, which in turn amplifies the UPR. ER-associated degradation (ERAD) is an UPR-dependent process; we also find that ERAD components (Sec61β, HRD1, p97/VCP, ubiquitin) are recruited to the ERQC, making it a likely site for retrotranslocation. In addition, we show that autophagy, suggested to play a role in elimination of aggregated proteins, is unrelated to protein accumulation in the ERQC.
KW - ER stress
KW - ER-associated degradation
KW - HRD1
KW - IRE1
KW - PERK
UR - http://www.scopus.com/inward/record.url?scp=34548651757&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2007.07.006
DO - 10.1016/j.yexcr.2007.07.006
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AN - SCOPUS:34548651757
SN - 0014-4827
VL - 313
SP - 3395
EP - 3407
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 16
ER -