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HRD1, an Important Player in Pancreatic β-Cell Failure and Therapeutic Target for Type 2 Diabetic Mice

Authors :
Yaqin Zhang
Tong Sun
Tijun Wu
Fang Chen
Wei Tang
Shuang Zhang
Yixue Shao
Xiao Han
Jiahui Wang
Jialiang Xu
Source :
Diabetes. 69:940-953
Publication Year :
2020
Publisher :
American Diabetes Association, 2020.

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.

Details

ISSN :
1939327X and 00121797
Volume :
69
Database :
OpenAIRE
Journal :
Diabetes
Accession number :
edsair.doi.dedup.....f43e2b00fcdb711adf34f2399fb224d7
Full Text :
https://doi.org/10.2337/db19-1060