HRD1, an Important Player in Pancreatic β-Cell Failure and Therapeutic Target for Type 2 Diabetic Mice
- 21 February 2020
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 69 (5), 940-953
- https://doi.org/10.2337/db19-1060
Abstract
Inadequate insulin secretion in response to glucose is an important factor for β-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 β-cell function, HRD1 elevation in a diabetic setting contributes to β-cell dysfunction. We report in this study the excessive HRD1 expression in islets from humans with T2D and T2D mice. Functional studies reveal that β-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 β-cell function. Furthermore, mechanistic assay results indicate that HRD1 is a novel E3 ubiquitin ligase that targets MafA for ubiquitination and degradation in diabetic β-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 β-cell dysfunction but also establish the therapeutic importance of targeting HRD1 in order to prevent MafA loss and suppress the development of T2D.Keywords
Funding Information
- National Natural Science Foundation of China (81420108007)
- National Natural Science Foundation of China (81830024)
- National Natural Science Foundation of China (81670705, 81702882)
- Natural Science Foundation of Jiangsu Province (BK20171056, BK20170106)
- Open Fund of the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China (KF-GN-201903)
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