The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα–SOD2 pathway

Yifan Xie, Yang Gao, Rifeng Gao, Wenlong Yang, Zheng Dong, Robb E. Moses, Aijun Sun, Xiaotao Li, Junbo Ge

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. REGγ is emerging as 11S proteasome activator of 20S proteasome to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner. Here, we found that REGγ was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts and angiotensin II (Ang II)-treated cardiomyocytes. REGγ deficiency ameliorated pressure overload-induced cardiac hypertrophy were associated with inhibition of cardiac reactive oxygen species (ROS) accumulation and suppression of protein phosphatase 2A catalytic subunit α (PP2Acα) decay. Mechanistically, REGγ interacted with and targeted PP2Acα for degradation directly, thereby leading to increase of phosphorylation levels and nuclear export of Forkhead box protein O (FoxO) 3a and subsequent of SOD2 decline, ROS accumulation, and cardiac hypertrophy. Introducing exogenous PP2Acα or SOD2 to human cardiomyocytes significantly rescued the REGγ-mediated ROS accumulation of Ang II stimulation in vitro. Furthermore, treatment with superoxide dismutase mimetic, MnTBAP prevented cardiac ROS production and hypertrophy features that REGγ caused in vivo, thereby establishing a REGγ–PP2Acα–FoxO3a–SOD2 pathway in cardiac oxidative stress and hypertrophy, indicates modulating the REGγ-proteasome activity may be a potential therapeutic approach in cardiac hypertrophy-associated disorders.

Original languageEnglish (US)
Pages (from-to)2952-2972
Number of pages21
JournalCell Death and Differentiation
Issue number10
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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