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

• Published in: The Journal of clinical investigation 2020-07, Vol.130 (7), p.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: Article
• Language: English
• Subjects: Adult; Age; Aged; Animals; Apoptosis; Autophagy; Beta cells; Biomedical research; Cell survival; Cell Survival - genetics; Clonal deletion; Degradation; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Endoplasmic Reticulum; Female; Glucose; HEK293 Cells; Humans; Hyperglycemia; Insulin; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Mice; Mice, Transgenic; Middle Aged; Phagocytosis; Physiology; Proteins; Proteins - genetics; Proteins - metabolism; Proteolysis; Quality control; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - metabolism; Ribonucleic acid; RNA; Signal Transduction; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI134874

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.