Ubiquitin-dependent rapid degradation conceals a cell-protective function of cytoplasmic SIRT3 against oxidative stress. (29th October 2021)

• Record Type: Journal Article
• Authors: Hayashi, Takashi; Matsushita, Takashi; Hisahara, Shin; Iwahara, Naotoshi; Kuno, Atsushi; Kunimoto, Risa; Hosoda, Ryusuke; Tanno, Masaya; Shimohama, Shun; Horio, Yoshiyuki
• Is Part Of: Journal of biochemistry. Volume 171:Number 2(2022)
• Page Start: 201
• Page End: 213
• Publication Date: 2021-10-29
• Subjects: neuronoxidative stressSIRT3ubiquitination; Biochemistry -- Periodicals; Biochemistry -- Periodicals; Electronic journals; 572.05
• DOI: 10.1093/jb/mvab119
• Languages: English
• ISSNs: 0021-924X

Abstract

Abstract: SIRT3 is an NAD + -dependent protein deacetylase localized in mitochondria. Several studies reported localization of SIRT3 in the cytoplasm or nucleus, but data of these studies were not consistent. We detected expression of mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs in the mouse brain, and we also found SIRT3 immunostaining of mitochondria and cytoplasm in the brain and cultured neural cells. However, expression levels of SIRT3ct in COS cells transfected with SIRT3ct cDNA were much lower than those of SIRT3mt. We found that SIRT3ct but not SIRT3mt was promptly degraded by ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by ubiquitination of NH2 -terminal methionine and partly by that of lysine residues of SIRT3ct. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2 O2 . H2 O2 treatment promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. Overexpression of SIRT3ct decreased cell death caused by H2 O2 at levels similar to those achieved by overexpression of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death caused by amyloid-β (Aβ), and overexpression of SIRT3ct suppressed the toxic function of Aβ in PC12 cells. These results indicate that SIRT3ct promotes cell survival under physiological and pathological conditions. Graphical Abstract: