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WWP2 regulates SIRT1-STAT3 acetylation and phosphorylation involved in hypertensive angiopathy.

ABSTRACT: WWP2 is a HECT-type E3 ubiquitin ligase that regulates various physiological and pathological activities by binding to different substrates, but its function and regulatory mechanism in vascular smooth muscle cells (VSMCs) are still unknown. Here, we clarified the role of WWP2 in the regulation of SIRT1-STAT3 and the impact of this regulatory process in VSMCs. We demonstrated that WWP2 expression was significantly increased in angiotensin II-induced VSMCs model. Knockdown of WWP2 significantly inhibited angiotensin II-induced VSMCs proliferation, migration and phenotypic transformation, whereas overexpression of WWP2 had opposite effects. In vivo experiments showed that vascular smooth muscle-specific WWP2 knockout mice significantly relieved angiotensin II-induced hypertensive angiopathy. Mechanistically, mass spectrometry and co-immunoprecipitation assays identified that WWP2 is a novel interacting protein of SIRT1 and STAT3. Moreover, WWP2 formed a complex with SIRT1-STAT3, inhibiting the interaction between SIRT1 and STAT3, then reducing the inhibitory effect of SIRT1 on STAT3, ensuing promoting STAT3-K685 acetylation and STAT3-Y705 phosphorylation in angiotensin II-induced VSMCs and mice. In conclusion, WWP2 modulates hypertensive angiopathy by regulating SIRT1-STAT3 and WWP2 suppression in VSMCs can alleviate hypertensive angiopathy vitro and vivo. These findings provide new insights into the treatment of hypertensive vascular diseases.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7417706 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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WWP2 regulates SIRT1-STAT3 acetylation and phosphorylation involved in hypertensive angiopathy.

Zhang Ying Y You Shilong S Tian Yichen Y Lu Saien S Cao Liu L Sun Yingxian Y Zhang Naijin N

Journal of cellular and molecular medicine 20200705 16

WWP2 is a HECT-type E3 ubiquitin ligase that regulates various physiological and pathological activities by binding to different substrates, but its function and regulatory mechanism in vascular smooth muscle cells (VSMCs) are still unknown. Here, we clarified the role of WWP2 in the regulation of SIRT1-STAT3 and the impact of this regulatory process in VSMCs. We demonstrated that WWP2 expression was significantly increased in angiotensin II-induced VSMCs model. Knockdown of WWP2 significantly i ...[more]

PMID: 32627301

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Project description:SIR2 is an NAD(+)-dependent deacetylase [1]-[3] implicated in the regulation of lifespan in species as diverse as yeast [4], worms [5], and flies [6]. We previously reported that the level of SIRT1, the mammalian homologue of SIR2 [7], [8], is coupled to the level of mitotic activity in cells both in vitro and in vivo[9]. Cells from long-lived mice maintained SIRT1 levels of young mice in tissues that undergo continuous cell replacement by proliferating stem cells. Changes in SIRT1 protein level were not associated with changes in mRNA level, suggesting that SIRT1 could be regulated post-transcriptionally. However, other than a recent report on sumoylation [10] and identification of SIRT1 as a nuclear phospho-protein by mass spectrometry [11], post-translational modifications of this important protein have not been reported.We identified 13 residues in SIRT1 that are phosphorylated in vivo using mass spectrometry. Dephosphorylation by phosphatases in vitro resulted in decreased NAD(+)-dependent deacetylase activity. We identified cyclinB/Cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates SIRT1. Mutation of two residues phosphorylated by Cyclin B/Cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in SIRT1-deficient cells [12], [13].Pharmacological manipulation of SIRT1 activity is currently being tested as a means of extending lifespan in mammals. Treatment of obese mice with resveratrol, a pharmacological activator of SIRT1, modestly but significantly improved longevity and, perhaps more importantly, offered some protection against the development of type 2 diabetes mellitus and metabolic syndrome [14]-[16]. Understanding the endogenous mechanisms that regulate the level and activity of SIRT1, therefore, has obvious relevance to human health and disease. Our results identify phosphorylation by cell cycle dependent kinases as a major mechanism controlling the level and function of this sirtuin and complement recent reports of factors that inhibit [17], [18] and activate [19] SIRT1 by protein-protein interactions.

Dataset Information

WWP2 regulates SIRT1-STAT3 acetylation and phosphorylation involved in hypertensive angiopathy.

Publications

WWP2 regulates SIRT1-STAT3 acetylation and phosphorylation involved in hypertensive angiopathy.

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