Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling.

Autor:	Shrestha N; Department of Molecular and Integrative Physiology, University of Michigan Medical School., Liu T; Life Sciences Institute, University of Michigan, and.; Department of Cell and Developmental Biology and., Ji Y; Department of Molecular and Integrative Physiology, University of Michigan Medical School., Reinert RB; Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Torres M; Department of Molecular and Integrative Physiology, University of Michigan Medical School., Li X; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China., Zhang M; College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan, USA., Tang CA; Immunology, Microenvironment, Metastasis Program, Wistar Institute, Philadelphia, Pennsylvania, USA., Hu CA; Immunology, Microenvironment, Metastasis Program, Wistar Institute, Philadelphia, Pennsylvania, USA., Liu C; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Naji A; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Liu M; Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.; Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China., Lin JD; Life Sciences Institute, University of Michigan, and.; Department of Cell and Developmental Biology and., Kersten S; Nutrition, Metabolism and Genomics group, Wageningen University, Wageningen, Netherlands., Arvan P; Department of Molecular and Integrative Physiology, University of Michigan Medical School.; Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA., Qi L; Department of Molecular and Integrative Physiology, University of Michigan Medical School.; Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2020 Jul 01; Vol. 130 (7), pp. 3499-3510.
DOI:	10.1172/JCI134874
Abstrakt:	β Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of β cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with β cell loss, but rather loss of β cell identity. Sel1L-Hrd1 ERAD controlled β cell identity via TGF-β signaling, in part by mediating the degradation of TGF-β receptor 1. Inhibition of TGF-β signaling in Sel1L-deficient β cells augmented the expression of β cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in β cells, providing a framework for therapies targeting distinct mechanisms of protein quality control.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu