title: SDF2L1 interacts with the ER-associated degradation machinery and retards the degradation of mutant proinsulin in pancreatic β-cells.
abstract: Stromal cell-derived factor 2-like 1 (SDF2L1) is an endoplasmic reticulum (ER)-localized protein whose function is undefined. Here we show that SDF2L1 protein levels are increased in response to ER stress-inducing compounds, but not other cell stressors that we tested in insulinoma cell lines. SDF2L1 protein levels were also induced by expression of misfolded proinsulin in insulinoma cells and in islets from diabetic mice. Immunoprecipitation and binding assays demonstrated that SDF2L1 interacts with the ER chaperone GRP78/BiP, the ER-associated degradation (ERAD) machinery and with misfolded proinsulin. Unexpectedly, knockdown of SDF2L1 in INS-1 (insulin 2 C96Y-GFP) cells increased the degradation kinetics of mutant proinsulin, suggesting that SDF2L1 regulates substrate availability for the ERAD system. We suggest that SDF2L1 increases the time that misfolded proteins have to achieve a correctly folded conformation and thus that SDF2L1 can act as a buffer for substrate availability for ERAD in pancreatic β-cells.
authors: Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, ON M5G 1L7, Canada.
authors: Akansha
authors: A
authors: Tiwari
authors: Irmgard
authors: I
authors: Schuiki
authors: Liling
authors: L
authors: Zhang
authors: Emma M
authors: EM
authors: Allister
authors: Michael B
authors: MB
authors: Wheeler
authors: Allen
authors: A
authors: Volchuk
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D060746:Endoplasmic Reticulum-Associated Degradation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011384:Proinsulin / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D008565:Membrane Proteins; D011384:Proinsulin; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C422105:SDF2L1 protein, human
keywords: ER associated degradation; ER stress; ERAD; Insulin; Pancreatic β-cells; Proinsulin; SDF2L1