Abstract
Mitophagy is a cellular quality-control pathway, which is essential for elimination of unhealthy mitochondria. While mitophagy is critical to pancreatic β-cell function, the posttranslational signals governing β-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 β-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 β-cell mitophagy, oxygen consumption, and insulin secretion. Indeed, patients treated with lenalidomide develop compromised β-cell function. Moreover, the β-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 β-cell function.
© 2017 by the American Diabetes Association.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Animals
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Cell Line
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Cells, Cultured
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Crosses, Genetic
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Endopeptidases / chemistry
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Endopeptidases / genetics
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Endopeptidases / metabolism*
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Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
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Endosomal Sorting Complexes Required for Transport / chemistry
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Endosomal Sorting Complexes Required for Transport / genetics
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Endosomal Sorting Complexes Required for Transport / metabolism*
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Enzyme Inhibitors / pharmacology
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Glucose / metabolism
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Humans
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Insulin / metabolism
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Insulin Secretion
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Insulin-Secreting Cells / cytology
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism*
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Lectins, C-Type / antagonists & inhibitors
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Lectins, C-Type / chemistry
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Lectins, C-Type / genetics
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Lectins, C-Type / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mitophagy* / drug effects
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Monosaccharide Transport Proteins / antagonists & inhibitors
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Monosaccharide Transport Proteins / chemistry
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Monosaccharide Transport Proteins / genetics
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Monosaccharide Transport Proteins / metabolism*
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Protein Multimerization / drug effects
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Protein Stability / drug effects
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Tissue Banks
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Tissue Culture Techniques
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Ubiquitin Thiolesterase / antagonists & inhibitors
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Ubiquitin Thiolesterase / chemistry
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Ubiquitin Thiolesterase / genetics
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Ubiquitin Thiolesterase / metabolism*
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Ubiquitin-Protein Ligases / antagonists & inhibitors
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination / drug effects
Substances
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Angiogenesis Inhibitors
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CLEC16A protein, human
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Endosomal Sorting Complexes Required for Transport
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Enzyme Inhibitors
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Insulin
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Lectins, C-Type
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Monosaccharide Transport Proteins
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Recombinant Fusion Proteins
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RNF41 protein, human
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Ubiquitin-Protein Ligases
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Endopeptidases
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USP8 protein, human
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Ubiquitin Thiolesterase
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Glucose