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HRD1, an Important Player in Pancreatic β-Cell Failure and Therapeutic Target for Type 2 Diabetic Mice
- 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.
- Subjects :
- Male
0301 basic medicine
Cytoplasm
Maf Transcription Factors, Large
Ubiquitin-Protein Ligases
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Cell
030209 endocrinology & metabolism
Cell Line
Mice
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Mice, Inbred NOD
Insulin-Secreting Cells
Diabetes mellitus
Internal Medicine
medicine
Animals
Humans
Insulin
RNA, Messenger
Glucose tolerance test
Gene knockdown
medicine.diagnostic_test
biology
Oncogene
Glucose Tolerance Test
medicine.disease
Ubiquitin ligase
Cell biology
Glucose
030104 developmental biology
medicine.anatomical_structure
Diabetes Mellitus, Type 2
Gene Expression Regulation
biology.protein
Subjects
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