Journal article
Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates beta-Cell Mitophagy
Diabetes (New York, N.Y.), Vol.67(2), pp.265-277
02/01/2018
DOI: 10.2337/db17-0321
PMCID: PMC5780060
PMID: 29180353
Abstract
Mitophagy is a cellular quality-control pathway, which is essential for elimination of unhealthy mitochondria. While mitophagy is critical to pancreatic beta-cell function, the posttranslational signals governing beta-cell mitochondrial turnover are unknown. Here, we report that ubiquitination is essential for the assembly of a mitophagy regulatory complex, comprised of the E3 ligase Nrdp1, the deubiquitinase enzyme USP8, and Clec16a, a mediator of beta-cell mitophagy with unclear function. We discover that the diabetes gene Clec16a encodes an E3 ligase, which promotes nondegradative ubiquitin conjugates to direct its mitophagy effectors and stabilize the Clec16a-Nrdp1-USP8 complex. Inhibition of the Clec16a pathway by the chemotherapeutic lenalidomide, a selective ubiquitin ligase inhibitor associated with new-onset diabetes, impairs beta-cell mitophagy, oxygen consumption, and insulin secretion. Indeed, patients treated with lenalidomide develop compromised beta-cell function. Moreover, the beta-cell Clec16a-Nrdp1-USP8 mitophagy complex is destabilized and dysfunctional after lenalidomide treatment as well as after glucolipotoxic stress. Thus, the Clec16a-Nrdp1-USP8 complex relies on ubiquitin signals to promote mitophagy and maintain mitochondrial quality control necessary for optimal beta-cell function.
Details
- Title: Subtitle
- Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates beta-Cell Mitophagy
- Creators
- Gemma Pearson - University of Michigan–Ann ArborBiaoxin Chai - University of Michigan–Ann ArborTracy Vozheiko - University of Michigan–Ann ArborXueying Liu - University of Michigan–Ann ArborMalathi Kandarpa - Division of Hematology and Oncology, Department of Internal Medicine, University of.Robert C. Piper - Roy J. and Lucille A. Carver College of MedicineScott A. Soleimanpour - University of Michigan–Ann Arbor
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.67(2), pp.265-277
- DOI
- 10.2337/db17-0321
- PMID
- 29180353
- PMCID
- PMC5780060
- NLM abbreviation
- Diabetes
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Publisher
- Amer Diabetes Assoc
- Number of pages
- 13
- Grant note
- P30CA086862 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R03DK106304 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) K08-DK-089117; R03-DK-106304; R01-DK-108921 / National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Brehm family Danish Diabetes Academy Novo Nordisk Foundation; Novocure Limited Central Society for Clinical and Translational Research CDA-2016-189; SRA-2018-539 / JDRF; Juvenile Diabetes Research Foundation Anthony family
- Language
- English
- Date published
- 02/01/2018
- Academic Unit
- Molecular Physiology and Biophysics; Medicine Administration; Internal Medicine
- Record Identifier
- 9984297615402771
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