Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 566502
Title ER-associated degradation is required for the maintenance of β cell identity via TGFβ signaling
Author(s) Shrestha, Neha; Liu, T.; Ji, Yewei; Reinert, Rachel B.; Torres, Mauricio; Zhang, M.; Tang, C.A.; Hu, C.A.; Liu, Chengyang; Naji, Ali; Lin, Jiandie D.; Kersten, Sander; Arvan, Peter; Qi, Ling; Hooiveld, Guido
Source Wageningen University & Research
Department(s) VLAG
Nutrition, Metabolism and Genomics
Publication type Dataset
Publication year 2020
Keyword(s) Mus musculus - GSE143757 - PRJNA601502
Abstract β cell apoptosis and dedifferentiation are two hotly-debated mechanisms underlying β cell loss in type 2 diabetes (T2D); however, the molecular drivers underlying such events remain largely unclear. Here, by performing a side-by-side comparison of mice carrying β cell-specific deletion of endoplasmic reticulum (ER)-associated degradation (ERAD) and autophagy, we report that while autophagy appears necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex is required for the maintenance of β cell maturation and identity. Notably, SEL1L expression is significantly reduced in human T2D islets compared to healthy human islets. At the single cell level, we demonstrate that Sel1L deficiency is not associated with β cell loss, but rather loss of β cell identity. Mechanistically, we find that Sel1L-Hrd1 ERAD controls β cell identity via TGFβ signaling, in part by mediating the degradation of TGF-β receptor 1 (TGFβRI). Inhibition of TGFβ signaling in Sel1L-deficient β cells augments the expression of β cell maturation markers and increases the total insulin content. Our data reveal profound but distinct pathogenic effects of two major proteolytic pathways in β cells, providing a new framework for therapies targeting distinct mechanisms of protein quality control
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