@article{dd4b95462a454369b5c26107818d95dc,
title = "Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling",
abstract = "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.",
author = "Neha Shrestha and Tongyu Liu and Yewei Ji and Reinert, {Rachel B.} and Mauricio Torres and Xin Li and Maria Zhang and Tang, {Chih Hang Anthony} and Hu, {Chih Chi Andrew} and Chengyang Liu and Ali Naji and Ming Liu and Lin, {Jiandie D.} and Sander Kersten and Peter Arvan and Ling Qi",
note = "Funding Information: We thank Richard Wojcikiewicz, Mark Huising, Alnawaz Rehemtul-la, Rajat Singh, Masaaki Komatsu, Keiji Tanaka, and Scott Solei-manpour for reagents and members of the Qi/Arvan laboratories for comments and technical assistance. Human sample analysis was performed with funding provided by the Human Pancreas Analysis Program (HPAP) (http://hpap.pmacs.upenn.edu/citation) (supported by the National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]) as part of the Human Islet Research Network (HIRN, RRID:SCR_014393; http://hirnetwork.org) (grant UC4 DK112217 to AN). Confocal microscopy and image analysis were completed at the Michigan Diabetes Research Center{\textquoteright}s Microscopy, Imaging and Cellular Physiology Core, supported by NIH NIDDK grant P30DK020572. This work was supported by NIH grants 1R01CA163910 (to CCAH), 1R24DK110973 (to PA), 1R01DK11174 (to PA and LQ), R01DK110047, and R01DK117639; Juvenile Diabetes Research Foundation grant 2-SRA-2018-539-A-B (to PA and LQ); and American Diabetes Association (ADA) grant 1-19-IBS-235 (to LQ). YJ is in part supported by American Heart Association Scientist Development grant 17SDG33670192 and Michigan Nutrition Obesity Research Center (MNORC) Pilot/ Feasibility grant (P30DK089503). RBR is supported by the Training Program in Endocrinology and Metabolism (5T32DK007245). MT was supported in part by the Pew Latin American Postdoctoral Fellowship. LQ is the recipient of Junior Faculty and Career Development Awards from the ADA. Publisher Copyright: Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = jul,
day = "1",
doi = "10.1172/JCI134874",
language = "English (US)",
volume = "130",
pages = "3499--3510",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "7",
}