Sel1L-Hrd1 ER-associated degradation maintains ß cell identity via TGF-ß signaling.
J Clin Invest
; 130(7): 3499-3510, 2020 07 01.
Article
in En
| MEDLINE
| ID: mdl-32182217
ß Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying ß 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 ß cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for ß cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of ß cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with ß cell loss, but rather loss of ß cell identity. Sel1L-Hrd1 ERAD controlled ß cell identity via TGF-ß signaling, in part by mediating the degradation of TGF-ß receptor 1. Inhibition of TGF-ß signaling in Sel1L-deficient ß cells augmented the expression of ß cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in ß cells, providing a framework for therapies targeting distinct mechanisms of protein quality control.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
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Proteins
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Transforming Growth Factor beta
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Ubiquitin-Protein Ligases
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Intracellular Signaling Peptides and Proteins
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Endoplasmic Reticulum
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Insulin-Secreting Cells
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Proteolysis
Type of study:
Risk_factors_studies
Limits:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
J Clin Invest
Year:
2020
Document type:
Article
Country of publication: