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DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation.

ABSTRACT: Imbalanced mitochondrial fission/fusion, a major cause of apoptotic cell death, often results from dysregulation of Drp1 phosphorylation of two serines, S616 and S637. Whereas kinases for Drp1-S616 phosphorylation are well-described, phosphatase(s) for its dephosphorylation remains unclear. Here, we show that dual-specificity phosphatase 6 (DUSP6) dephosphorylates Drp1-S616 independently of its known substrates ERK1/2. DUSP6 keeps Drp1-S616 phosphorylation levels low under normal conditions. The stability and catalytic function of DUSP6 are maintained through conjugation of small ubiquitin-like modifier-1 (SUMO1) and SUMO2/3 at lysine-234 (K234), which is disrupted during oxidation through transcriptional up-regulation of SUMO-deconjugating enzyme, SENP1, causing DUSP6 degradation by ubiquitin-proteasome. deSUMOylation underlies DUSP6 degradation, Drp1-S616 hyperphosphorylation, mitochondrial fragmentation, and apoptosis induced by H₂O₂ in cultured cells or brain ischemia/reperfusion in mice. Overexpression of DUSP6, but not the SUMOylation-deficient DUSP6^K234R mutant, protected cells from apoptosis. Thus, DUSP6 exerts a cytoprotective role by directly dephosphorylating Drp1-S616, which is disrupted by deSUMOylation under oxidation.

SUBMITTER: Ma R

PROVIDER: S-EPMC7096176 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation.

Ma Ruining R Ma Lina L Weng Weiji W Wang Yingping Y Liu Huiqing H Guo Rongjun R Gao Yingwei Y Tu Jun J Xu Tian-Le TL Cheng Jinke J Zhu Michael X MX Zhou Aiwu A Li Yong Y Li Yong Y

Science advances 20200325 13

Imbalanced mitochondrial fission/fusion, a major cause of apoptotic cell death, often results from dysregulation of Drp1 phosphorylation of two serines, S616 and S637. Whereas kinases for Drp1-S616 phosphorylation are well-described, phosphatase(s) for its dephosphorylation remains unclear. Here, we show that dual-specificity phosphatase 6 (DUSP6) dephosphorylates Drp1-S616 independently of its known substrates ERK1/2. DUSP6 keeps Drp1-S616 phosphorylation levels low under normal conditions. The ...[more]

PMID: 32232156

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Dataset Information

DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation.

Publications

DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation.

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