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USP8 binds RNF41 and CLEC16A. 28 / 28
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"Furthermore, we observed that both Nrdp1 stability and ubiquitination were reduced in Min6 β-cells after palmitate treatment (Fig. 6D), thus demonstrating effects consistent with impact on the Clec16a pathway to maintain the upstream mitophagy complex.To determine whether glucolipotoxicity affects Clec16a to impact formation of the Clec16a-Nrdp1-USP8 complex, we overexpressed Clec16a in palmitate-treated Min6 β-cells."
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"Further, we observe that diabetogenic metabolic stressors, including elevated glucose and fatty acids, destabilize the CLEC16A, RNF41, and USP8 complex and lead to beta-cell apoptosis."
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"Given our findings suggesting that both Nrdp1 stability and ubiquitination regulate formation of the Clec16a-Nrdp1-USP8 complex, we next measured Nrdp1 levels after palmitate treatment in primary islets."
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"We next assessed the role of Nrdp1 ubiquitination on formation of the Clec16a-Nrdp1-USP8 complex."
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"Previous observations of defective mitochondrial integrity after glucolipotoxicity (7,36), coupled with our findings here of glucolipotoxicity-mediated destabilization of the Clec16a-Nrdp1-USP8 complex, could inspire future in vivo studies to evaluate the importance of dysfunctional mitophagy to β-cell failure in diabetes."
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"To determine the importance of maintenance of the Clec16a-Nrdp1-USP8 complex to β-cell survival during glucolipotoxicity, we assessed β-cell apoptosis by cleaved caspase-3 levels after Clec16a overexpression."
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"Given the importance of ubiquitination to Clec16a-Nrdp1-USP8 complex assembly, we hypothesized that specific ubiquitination of Nrdp1 may influence formation of the Clec16a-Nrdp1-USP8 complex."
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"Thus, the beta-cell mitophagy pathway requires ubiquitin signals to stabilize the CLEC16A, RNF41, and USP8 complex and maintain mitochondrial quality control."
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"While the dynamics of the Clec16a-Nrdp1-USP8 complex are still a mystery, it is clear that Clec16a-mediated ubiquitination orchestrates mitophagic flux in β-cells.Our discovery of Clec16a as an E3 ligase, whose function is inhibited by lenalidomide, expands our insight into its functional role in mitophagy."
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"Furthermore, Clec16a-mediated Nrdp1 ubiquitination is essential for assembly of the Clec16a-Nrdp1-USP8 complex and preservation of β-cell function ( xref )."
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"To determine whether glucolipotoxicity affects Clec16a to impact formation of the Clec16a-Nrdp1-USP8 complex, we overexpressed Clec16a in palmitate-treated Min6 β-cells."
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"Collectively, these findings suggest that functional ubiquitination is necessary for maintaining levels of the constituents of the Clec16a-Nrdp1-USP8 complex as well as providing vital signals for complex assembly.USP8 shares functional overlap with Clec16a/Nrdp1 in the regulation of mitophagic flux, coinciding in their opposing regulation of the E3 ligase Parkin, a critical effector in mitophagy (34)."
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"Given our findings suggesting that both Nrdp1 stability and ubiquitination regulate formation of the Clec16a-Nrdp1-USP8 complex, we next measured Nrdp1 levels after palmitate treatment in primary islets."
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"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, and USP8 complex."
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"Lenalidomide impaired Nrdp1-USP8 interaction in Min6 β-cells (Fig. 5E), suggesting that Clec16a-mediated ubiquitination maintains the Clec16a-Nrdp1-USP8 complex as well as β-cell function."
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"While Clec16a enhanced Nrdp1-USP8 complex assembly, addition of the ubiquitin KO mutant reduced Nrdp1 levels as well as Nrdp1 interaction with both Clec16a and USP8 ( xref )."
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"Thus, the Clec16a-Nrdp1-USP8 complex relies on ubiquitin signals to promote mitophagy and maintain mitochondrial quality control necessary for optimal beta-cell function."
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"Thus, the Clec16a, Nrdp1, and USP8 complex relies on ubiquitin signals to promote mitophagy and maintain mitochondrial quality control necessary for optimal beta-cell function."
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"We next assessed the role of Nrdp1 ubiquitination on formation of the Clec16a-Nrdp1-USP8 complex."
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"Clec16a, USP8, and Nrdp1 Interact in a Ubiquitin-Dependent Complex."
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"These results suggest, again, that Clec16a drives assembly of the Clec16a-Nrdp1-USP8 complex by providing essential ubiquitin signals and stabilizing its component proteins."
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"We previously confirmed the formation of the CLEC16A-NRDP1-USP8 mitophagy complex in pancreatic beta cells by several methodologies, including co-immunoprecipitation experiments, cell-free interaction studies, and in vitro as well as cell-based ubiquitination assays, and demonstrated how this complex drives regulated mitophagic flux xref , xref ."
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"These results suggest, again, that Clec16a drives assembly of the Clec16a-Nrdp1-USP8 complex by providing essential ubiquitin signals and stabilizing its component proteins.To determine whether the Clec16a-Nrdp1-USP8 axis regulates β-cell function, we assessed the role of Clec16a-mediated ubiquitination on GSIS in Min6 β-cells."
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"We demonstrate that Clec16a is an E3 ubiquitin ligase, which ubiquitinates Nrdp1 to promote assembly of the Clec16a-Nrdp1-USP8 mitophagy complex."
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"Furthermore, Clec16a-mediated Nrdp1 ubiquitination is essential for assembly of the Clec16a-Nrdp1-USP8 complex and preservation of β-cell function (Fig. 7)."
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"Given the importance of ubiquitination to Clec16a-Nrdp1-USP8 complex assembly, we hypothesized that specific ubiquitination of Nrdp1 may influence formation of the Clec16a-Nrdp1-USP8 complex."
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"To clarify whether impaired ubiquitination affected the Clec16a-Nrdp1-USP8 complex as a result of reduced levels of constituents or by impaired complex assembly, we also doubled the amount of Flag-Clec16a plasmid in the presence of KO ubiquitin, resulting in increased levels of Clec16a, USP8, and Nrdp1 (Fig. 4E, lane ++)."
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"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."
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