SIRT2 regulates oxidative stress-induced cell death through deacetylation of c-Jun NH2-terminal kinase

Abstract

c-Jun NH-terminal kinases (JNKs) are responsive to stress stimuli and their activation regulate key cellular functions, including cell survival, growth, differentiation and aging. Previous studies demonstrate that activation of JNK requires dual phosphorylation by the mitogen-activated protein kinase kinases. However, other post-translational mechanisms involved in regulating the activity of JNK have been poorly understood. In this work, we studied the functional significance of reversible lysine acetylation in regulating the kinase activity of JNK. We found that the acetyl transferase p300 binds to, acetylates and inhibits kinase activity of JNK. Using tandem mass spectrometry, molecular modelling and molecular dynamics simulations, we found that acetylation of JNK at Lys153 would hinder the stable interactions of the negatively charged phosphates and prevent the adenosine binding to JNK. Our screening for the deacetylases found SIRT2 as a deacetylase for JNK. Mechanistically, SIRT2-dependent deacetylation enhances ATP binding and enzymatic activity of JNK towards c-Jun. Furthermore, SIRT2-mediated deacetylation favours the phosphorylation of JNK by MKK4, an upstream kinase. Our results indicate that deacetylation of JNK by SIRT2 promotes oxidative stress-induced cell death. Conversely, SIRT2 inhibition attenuates HO-mediated cell death in HeLa cells. SIRT2-deficient (SIRT2-KO) mice exhibit increased acetylation of JNK, which is associated with markedly reduced catalytic activity of JNK in the liver. Interestingly, SIRT2-KO mice were resistant to acetaminophen-induced liver toxicity. SIRT2-KO mice show lower cell death, minimal degenerative changes, improved liver function and survival following acetaminophen treatment. Overall, our work identifies SIRT2-mediated deacetylation of JNK as a critical regulator of cell survival during oxidative stress.

The role of SIRT2 in cancer: A novel therapeutic target

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SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation

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“…SIRT1 alters methylation of histones via recruitment and activation of histone methyltransferase ( Jing and Lin, 2015 ). Sirtuins also directly deacetylate histones, transcription factors, and coregulators thereby altering gene expression through changes in chromatin accessibility ( Bosch-Presegue and Vaquero, 2015 ; Gorisch et al., 2005 ; Jing and Lin, 2015 ; Sarikhani et al., 2018a , 2018b ). These results demonstrate that sustained activation of AMPK in iPSC-derived cardiomyocytes during early differentiation led to epigenetic changes mediated by sirtuins.…”