Related Experiment Video
Updated: Dec 26, 2025
Methods to Assess Beta Cell Death Mediated by Cytotoxic T Lymphocytes
Published on: June 16, 2011
Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling
Neha Shrestha1, Tongyu Liu2,3, Yewei Ji1
1Department of Molecular and Integrative Physiology, University of Michigan Medical School.
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.
Insights
The Sel1L-Hrd1 ERAD complex maintains pancreatic beta cell identity in type 2 diabetes by regulating TGF-β signaling. Its deficiency causes loss of beta cell identity, not cell death.
Area of Science:
- Endocrinology
- Molecular Biology
- Diabetes Research
Background:
- Type 2 diabetes involves beta cell loss, potentially via apoptosis or dedifferentiation.
- Molecular mechanisms driving these beta cell changes are not fully understood.
- Protein quality control pathways like ER-associated degradation (ERAD) and autophagy are crucial for cell function.
Purpose of the Study:
- To compare the roles of ERAD and autophagy in pancreatic beta cell survival and identity.
- To elucidate the molecular drivers of beta cell dysfunction in type 2 diabetes.
Main Methods:
- Generated mice with beta cell-specific deletion of ERAD and autophagy.
- Utilized single-cell RNA-sequencing (scRNA-Seq) to analyze gene expression.
- Investigated the role of TGF-β signaling in beta cell identity.
Main Results:
- Autophagy is essential for beta cell survival.
- The Sel1L-Hrd1 ERAD complex is critical for maintaining beta cell maturation and identity.
- Sel1L deficiency leads to loss of beta cell identity, not apoptosis.
- Sel1L-Hrd1 ERAD regulates beta cell identity through TGF-β signaling, partly via degrading TGF-β receptor 1.
- Inhibiting TGF-β signaling in Sel1L-deficient cells improved beta cell maturation markers and insulin content.
Conclusions:
- Distinct proteolytic pathways have different pathogenic effects in beta cells.
- The Sel1L-Hrd1 ERAD pathway is vital for preserving beta cell identity.
- Targeting protein quality control mechanisms, particularly ERAD and TGF-β signaling, offers potential therapeutic strategies for type 2 diabetes.
More Related Videos
Related Concept Videos
01:16TGF - β Signaling Pathway
01:28Insulin: The Receptor and Signaling Pathways
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
01:58Cell Specific Gene Expression
01:05Insulin Secretory Vesicles