title: Cellular inhibitor of apoptosis protein-1 (cIAP1) plays a critical role in β-cell survival under endoplasmic reticulum stress: promoting ubiquitination and degradation of C/EBP homologous protein (CHOP).
abstract: Lipotoxicity in pancreatic β-cells, arising from excess free fatty acid-induced endoplasmic reticulum (ER) stress response, has been recognized as a key pathogenic factor causing loss of β-cell mass and contributing to type 2 diabetes. However, how the adaptive ER stress response causes cell death remains enigmatic. We report herein a critical role of cellular inhibitor of apoptosis protein-1 (cIAP1) in controlling β-cell survival under ER stress. While both palmitate and palmitoleate induced an overt ER stress response, lipotoxicity was only observed in β-cells exposed to palmitate but not palmitoleate. Interestingly, cells treated with palmitoleate exerted a sustainable level of cIAP1, whereas the protein quickly degraded following palmitate treatment. Enforced overexpression of cIAP1 prevented palmitate-induced cell death. In contrast, siRNA-mediated knockdown of cIAP1 in β-cells or knock-out of cIap1 in mouse embryonic fibroblasts not only increased palmitate-induced apoptosis, but also committed cells to death in response to the nontoxic palmitoleate treatment. Of importance, we found that cIAP1 functions as an E3 ubiquitin ligase promoting ubiquitination and degradation of C/EBP homologous protein (CHOP), a key mediator of ER stress-induced cell death. These findings define a novel mechanism for β-cell survival under ER stress and help to identify targets for therapeutic intervention against lipotoxicity in β-cells.
authors: Signal Transduction Program, Centenary Institute, Sydney Medical School, University of Sydney, Sydney, 2042 Australia.
authors: Yanfei
authors: Y
authors: Qi
authors: Pu
authors: P
authors: Xia
mesh_terms: D000818:Animals; D002470:Cell Survival; D003920:Diabetes Mellitus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D019308:Palmitic Acid / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D051742:Transcription Factor CHOP / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry; D056811:Unfolded Protein Response
chemical_list: C497249:DDIT3 protein, human; D051034:Inhibitor of Apoptosis Proteins; D025801:Ubiquitin; D051742:Transcription Factor CHOP; D019308:Palmitic Acid; D044767:Ubiquitin-Protein Ligases