| First Author | Wu T | Year | 2020 |
| Journal | Diabetes | Volume | 69 |
| Issue | 5 | Pages | 940-953 |
| PubMed ID | 32086291 | Mgi Jnum | J:291668 |
| Mgi Id | MGI:6432055 | Doi | 10.2337/db19-1060 |
| Citation | Wu T, et al. (2020) HRD1, an Important Player in Pancreatic beta-Cell Failure and Therapeutic Target for Type 2 Diabetic Mice. Diabetes 69(5):940-953 |
| abstractText | Inadequate insulin secretion in response to glucose is an important factor for beta-cell failure in type 2 diabetes (T2D). Although HMG-CoA reductase degradation 1 (HRD1), a subunit of the endoplasmic reticulum-associated degradation complex, plays a pivotal role in beta-cell function, HRD1 elevation in a diabetic setting contributes to beta-cell dysfunction. We report in this study the excessive HRD1 expression in islets from humans with T2D and T2D mice. Functional studies reveal that beta-cell-specific HRD1 overexpression triggers impaired insulin secretion that will ultimately lead to severe hyperglycemia; by contrast, HRD1 knockdown improves glucose control and response in diabetic models. Proteomic analysis results reveal a large HRD1 interactome, which includes v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), a master regulator of genes implicated in the maintenance of beta-cell function. Furthermore, mechanistic assay results indicate that HRD1 is a novel E3 ubiquitin ligase that targets MafA for ubiquitination and degradation in diabetic beta-cells, resulting in cytoplasmic accumulation of MafA and in the reduction of its biological function in the nucleus. Our results not only reveal the pathological importance of excessive HRD1 in beta-cell dysfunction but also establish the therapeutic importance of targeting HRD1 in order to prevent MafA loss and suppress the development of T2D. |
