Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 7, Pages 3499-3510Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI134874
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Funding
- Human Pancreas Analysis Program (HPAP) (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]) as part of the Human Islet Research Network (HIRN) [SCR_014393, UC4 DK112217]
- NIH NIDDK [P30DK020572]
- NIH [1R01CA163910, 1R24DK110973, 1R01DK11174, R01DK110047, R01DK117639]
- Juvenile Diabetes Research Foundation [2-SRA-2018-539A-B]
- American Diabetes Association (ADA) [1-19-IBS-235]
- American Heart Association Scientist Development [17SDG33670192]
- Michigan Nutrition Obesity Research Center (MNORC) Pilot/Feasibility grant [P30DK089503]
- Training Program in Endocrinology and Metabolism [5T32DK007245]
- Pew Latin American Postdoctoral Fellowship
- ADA
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beta Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying beta 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 beta cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for II cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of beta cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with beta cell loss, but rather loss of beta cell identity. Sel1L-Hrd1ERAD controlled II cell identity via TGF-beta signaling, in part by mediating the degradation of TGF-beta receptor 1. Inhibition of TGF-beta signaling in Sel1L-deficient beta cells augmented the expression of II cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in beta cells, providing a framework for therapies targeting distinct mechanisms of protein quality control.
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