Selective targeting of ubiquitination and degradation of PARP1 by E3 ubiquitin ligase WWP2 regulates isoproterenol-induced cardiac remodeling.

Cell Death and Differentiation
Naijin ZhangYingxian Sun

Abstract

The elevated expression of poly(ADP-ribose) polymerase-1 (PARP1) and increased PARP1 activity, namely, poly(ADP-ribosyl)ation (PARylation), have been observed in cardiac remodeling, leading to extreme energy consumption and myocardial damage. However, the mechanisms underlying the regulation of PARP1 require further study. WWP2, a HECT-type E3 ubiquitin ligase, is highly expressed in the heart, but its function there is largely unknown. Here, we clarified the role of WWP2 in the regulation of PARP1 and the impact of this regulatory process on cardiac remodeling. We determined that the knockout of WWP2 specifically in myocardium decreased the level of PARP1 ubiquitination and increased the effects of isoproterenol (ISO)-induced PARP1 and PARylation, in turn aggravating ISO-induced myocardial hypertrophy, heart failure, and myocardial fibrosis. Similar findings were obtained in a model of ISO-induced H9c2 cells with WWP2 knockdown, while the reexpression of WWP2 significantly increased PARP1 ubiquitination and decreased PAPR1 and PARylation levels. Mechanistically, coimmunoprecipitation results identified that WWP2 is a novel interacting protein of PARP1 and mainly interacts with its BRCT domain, thus mediating the degradation of...Continue Reading

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Citations

Jan 19, 2021·The FEBS Journal·Kanmin Mao, Guo Zhang
Mar 19, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nataša IlićMichael Blank
May 25, 2021·Journal of Cellular and Molecular Medicine·Boquan WuNaijin Zhang
Jul 3, 2021·International Journal of Molecular Sciences·Jun GotoMasafumi Watanabe

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Methods Mentioned

BETA
ubiquitination
transfection
immunoprecipitation
coimmunoprecipitation
PARylation

Software Mentioned

SPSS
Image J

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