Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling
| Autor: | Xin Li, Neha Shrestha, Rachel B. Reinert, Maria Zhang, Peter Arvan, Ali Naji, Chih-Hang Anthony Tang, Tongyu Liu, Chih-Chi Andrew Hu, Jiandie D. Lin, Ling Qi, Yewei Ji, Ming Liu, Mauricio Torres, Sander Kersten, Chengyang Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine Cell Survival Ubiquitin-Protein Ligases medicine.medical_treatment Receptor Transforming Growth Factor-beta Type I Mice Transgenic Endoplasmic-reticulum-associated protein degradation Endoplasmic Reticulum Cell Maturation Mice 03 medical and health sciences Voeding Metabolisme en Genomica 0302 clinical medicine Voeding Transforming Growth Factor beta Insulin-Secreting Cells medicine Animals Humans Life Science Receptor Nutrition Aged VLAG Chemistry Insulin Autophagy Intracellular Signaling Peptides and Proteins Proteins General Medicine Metabolism Middle Aged Metabolism and Genomics Cell biology HEK293 Cells 030104 developmental biology Diabetes Mellitus Type 2 Metabolisme en Genomica 030220 oncology & carcinogenesis Proteolysis Female Protein folding Nutrition Metabolism and Genomics Signal Transduction Research Article Transforming growth factor |
| Zdroj: | The Journal of Clinical Investigation 130 (2020) 7 The Journal of Clinical Investigation, 130(7), 3499-3510 J Clin Invest |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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