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Type: Journal article
Title: Limitation of individual folding resources in the ER leads to outcomes distinct from the unfolded protein response
Author: Eletto, D.
Maganty, A.
Eletto, D.
Dersh, D.
Makarewich, C.
Biswas, C.
Paton, J.
Paton, A.
Doroudgar, S.
Glembotski, C.
Argon, Y.
Citation: Journal of Cell Science, 2012; 125(20):4865-4875
Publisher: Company of Biologists Ltd
Issue Date: 2012
ISSN: 0021-9533
Statement of
Davide Eletto, Avinash Maganty, Daniela Eletto, Devin Dersh, Catherine Makarewich, Chhanda Biswas, James C. Paton, Adrienne W. Paton, Shirin Doroudgar, Christopher C. Glembotski and Yair Argon
Abstract: ER stress leads to upregulation of multiple folding and quality control components, known as the unfolded protein response (UPR). Glucose Regulated Protein 78 (GRP78) (also known as binding immunoglobulin protein, BiP, and HSPA5) and GRP94 are often upregulated coordinately as part of this homeostatic response. Given that endoplasmic reticulum (ER) chaperones have distinct sets of clients, we asked how cells respond to ablation of individual chaperones. The cellular responses to silencing BiP, GRP94, HSP47, PDIA6 and OS-9, were distinct. When BiP was silenced, a widespread UPR was observed, but when GRP94 was either inhibited or depleted by RNA interference (RNAi), the expression of only some genes was induced, notably those encoding BiP and protein disulfide isomerase A6 (PDIA6). Silencing of HSP47 or OS-9 did not lead to any compensatory induction of other genes. The selective response to GRP94 depletion was distinct from a typical ER stress response, both because other UPR target genes were not affected and because the canonical UPR signaling branches were not activated. The response to silencing of GRP94 did not preclude further UPR induction when chemical stress was imposed. Importantly, re-expression of wild-type GRP94 in the silenced cells prevented the upregulation of BiP and PDIA6, whereas re-expression of an ATPase-deficient GRP94 mutant did not, indicating that cells monitor the activity state of GRP94. These findings suggest that cells are able to distinguish among folding resources and generate distinct responses.
Keywords: Hela Cells; NIH 3T3 Cells; Animals; Humans; Mice; Membrane Glycoproteins; Heat-Shock Proteins; Signal Transduction; Gene Silencing; Protein Folding; Protein Disulfide-Isomerases; Unfolded Protein Response; Endoplasmic Reticulum Stress
Rights: Copyright 2012. Published by The Company of Biologists Ltd.
RMID: 0020123502
DOI: 10.1242/jcs.108928
Appears in Collections:Molecular and Biomedical Science publications

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