Sel1L-Hrd1 ER-associated degradation maintains [beta] cell identity via TGF-[beta] signaling

• Published in: The Journal of clinical investigation Vol. 130; no. 7; pp. 3499 - 3510
• Main Authors: Shrestha, Neha, Liu, Tongyu, Ji, Yewei, Reinert, Rachel B, Torres, Mauricio, Li, Xin, Zhang, Maria, Tang, Chih-Hang Anthony, Hu, Chih-Chi Andrew, Liu, Chengyang, Naji, Ali, Liu, Ming, Lin, Jiandie D, Kersten, Sander, Arvan, Peter, Qi, Ling
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01.07.2020
• Subjects: Analysis; Bone morphogenetic proteins; International economic relations; Pancreatic beta cells; RNA sequencing; Software industry; Transforming growth factors; Type 2 diabetes; United States; Pennsylvania
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI134874

[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 [beta] 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-Hrd1 ERAD controlled [beta] 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 [beta] 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.