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| Status |
Public on Jun 29, 2020 |
| Title |
ER-associated degradation is required for the maintenance of β cell identity via TGFβ signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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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| Overall design |
Gene expression was profiled in pancreatic islets isolated from 5-week-old wildtype and β cell-specific Sel1L-deficient mice.
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| Contributor(s) |
Shrestha N, Liu T, Ji Y, Reinert R, Torres M, Zhang M, Tang CA, Hu CA, Liu C, Naji A, Lin J, Kersten S, Arvan P, Qi L |
| Citation(s) |
32182217 |
| Submission date |
Jan 15, 2020 |
| Last update date |
Jul 01, 2020 |
| Contact name |
Guido Hooiveld |
| E-mail(s) |
guido.hooiveld@wur.nl
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| Organization name |
Wageningen University
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| Department |
Div. Human Nutrition & Health
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| Lab |
Nutrition, Metabolism & Genomics Group
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| Street address |
HELIX, Stippeneng 4
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| City |
Wageningen |
| ZIP/Postal code |
NL-6708WE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL17400 |
[MoGene-2_1-st] Affymetrix Mouse Gene 2.1 ST Array [transcript (gene) version] |
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| Samples (6)
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| GSM4274227 |
pancreatic islets, isolated from wildtype mouse, replicate 1 |
| GSM4274228 |
pancreatic islets, isolated from wildtype mouse, replicate 2 |
| GSM4274229 |
pancreatic islets, isolated from wildtype mouse, replicate 3 |
| GSM4274230 |
pancreatic islets, isolated from β cell-specific Sel1L-deficient mouse, replicate 1 |
| GSM4274231 |
pancreatic islets, isolated from β cell-specific Sel1L-deficient mouse, replicate 2 |
| GSM4274232 |
pancreatic islets, isolated from β cell-specific Sel1L-deficient mouse, replicate 3 |
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| Relations |
| BioProject |
PRJNA601502 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE143757_RAW.tar |
27.6 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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