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

Neha Shrestha, Tongyu Liu, Yewei Ji, Rachel B. Reinert, Mauricio Torres, Xin Li, Maria Zhang, Chih Hang Anthony Tang, Chih Chi Andrew Hu, Chengyang Liu, Ali Naji, Ming Liu, Jiandie D. Lin, Sander Kersten, Peter Arvan, Ling Qi

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3499-3510
Number of pages12
JournalJournal of Clinical Investigation
Volume130
Issue number7
DOIs
StatePublished - Jul 1 2020

ASJC Scopus subject areas

  • Medicine(all)

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