HRD1 an important player in pancreatic β-cell failure and therapeutic target for type 2 diabetic mice.

Diabetes 2020 Feb 21. Epub 2020 Feb 21.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China.

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 (ERAD) complex, plays a pivotal role in β-cell function, HRD1 elevation in a diabetic setting contributes to β-cell dysfunction. We report herein the excessive HRD1 expression in T2D human and mice islets. 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 MafA (v-maf musculoaponeurotic fibrosarcoma oncogene homologue A), 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.

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Source
http://dx.doi.org/10.2337/db19-1060DOI Listing
February 2020

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