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.
Keywords:
Beta cells; Cell Biology; Diabetes; Metabolism; Protein misfolding.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Animals
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Cell Survival / genetics
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / pathology
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Endoplasmic Reticulum*
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Female
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HEK293 Cells
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Humans
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Insulin-Secreting Cells / metabolism*
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Insulin-Secreting Cells / pathology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Male
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Mice
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Mice, Transgenic
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Middle Aged
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Proteins / genetics
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Proteins / metabolism*
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Proteolysis*
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Receptor, Transforming Growth Factor-beta Type I / genetics
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Receptor, Transforming Growth Factor-beta Type I / metabolism
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Signal Transduction*
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Intracellular Signaling Peptides and Proteins
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Proteins
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SEL1L protein, human
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Sel1h protein, mouse
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Transforming Growth Factor beta
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SYVN1 protein, human
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Syvn1 protein, mouse
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Ubiquitin-Protein Ligases
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, mouse