Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage.

Jiaxiang Shao,Qian Reuben Xie,Xiao Yang,Weiliang Xia,Tengyuan Liu,Tingting Zhang

doi:10.1007/s13238-016-0257-6

Abstract

SIRT6 is a NAD+-dependent histone deacetylase and has been implicated in the regulation of genomic stability, DNA repair, metabolic homeostasis and several diseases. The effect of SIRT6 in cerebral ischemia and oxygen/glucose deprivation (OGD) has been reported, however the role of SIRT6 in oxidative stress damage remains unclear. Here we used SH-SY5Y neuronal cells and found that overexpression of SIRT6 led to decreased cell viability and increased necrotic cell death and reactive oxygen species (ROS) production under oxidative stress. Mechanistic study revealed that SIRT6 induced autophagy via attenuation of AKT signaling and treatment with autophagy inhibitor 3-MA or knockdown of autophagy-related protein Atg5 rescued H2O2-induced neuronal injury. Conversely, SIRT6 inhibition suppressed autophagy and reduced oxidative stress-induced neuronal damage. These results suggest that SIRT6 might be a potential therapeutic target for neuroprotection.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0257-6) contains supplementary material, which is available to authorized users.

Highlights

IntroductionSirtuins are a family of NAD+-dependent histone deacetylases involved in diverse cellular functions including
Sirtuins are a family of NAD+-dependent histone deacetylases involved in diverse cellular functions includingElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.inflammation, energy metabolism, stress resistance and cancer (Haigis and Sinclair, 2010)
A recent study has reported that SIRT6 is associated with high mobility group box-1 (HMGB1) release after cerebral ischemia, but knockdown of SIRT6 has no effect on neuronal cell death induced by oxygen and glucose deprivation (OGD) (Lee et al, 2013b)

Summary

Introduction

Sirtuins are a family of NAD+-dependent histone deacetylases involved in diverse cellular functions including. Inflammation, energy metabolism, stress resistance and cancer (Haigis and Sinclair, 2010). There are seven mammalian sirtuins with varied subcellular localizations and enzymatic activities (Michishita et al, 2005). SIRT6 is predominantly localized in the nucleus, functioning as an ADP-ribosyltransferase and NAD+-dependent deacetylase (Liszt et al, 2005; Michishita et al, 2008; Feldman et al, 2013). SIRT6 plays an important role in genomic stability, DNA repair, metabolic homeostasis and diseases such as obesity, cardiac hypertrophy and cancer (Liu et al, 2013; Kugel and Mostoslavsky, 2014). Since oxidative stress is a key mediator of tissue damage after ischemia-reperfusion, the role of SIRT6 in oxidative stress-induced neuronal injury remains to be investigated

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