SIRT2 suppresses expression of inflammatory factors via Hsp90-glucocorticoid receptor signalling.

Kai Sun,Adil J Nazarali,Shaoping Ji,Ao Xu,Yao Lin,Na Fang,Xuan Wang,Xiaofang Zhao

doi:10.1111/jcmm.15365

Abstract

SIRT2 is a NAD+‐dependent deacetylase that deacetylates a diverse array of protein substrates and is involved in many cellular processes, including regulation of inflammation. However, its precise role in the inflammatory process has not completely been elucidated. Here, we identify heat‐shock protein 90α (Hsp90α) as novel substrate of SIRT2. Functional investigation suggests that Hsp90 is deacetylated by SIRT2, such that overexpression and knock‐down of SIRT2 altered the acetylation level of Hsp90. This subsequently resulted in disassociation of Hsp90 with glucocorticoid receptor (GR), and translocation of GR to the nucleus. This observation was further confirmed by glucocorticoid response element (GRE)‐driven reporter assay. Nuclear translocation of GR induced by SIRT2 overexpression repressed the expression of inflammatory cytokines, which were even more prominent under lipopolysaccharide (LPS) stimulation. Conversely, SIRT2 knock‐down resulted in the up‐regulation of cytokine expression. Mutation analysis indicated that deacetylation of Hsp90 at K294 is critical for SIRT2‐mediated regulation of cytokine expression. These data suggest that SIRT2 reduces the extent of LPS‐induced inflammation by suppressing the expression of inflammatory factors via SIRT2‐Hsp90‐GR axis.

Highlights

SIRT2 is an NAD+-dependent deacetylase that belongs to the Sirtuin family, which consists of 7 members in humans(SIRT1-7)
SIRT2 overexpression, which led to a decrease in the association between Hsp[90] and glucocorticoid receptor (GR) resulted in translocation of the GR to the nucleus
SIRT2 knock-down, which led to an increase in the association between Hsp[90] and GR resulted in GR remaining predominately in the cytoplasm

Summary

| INTRODUCTION

SIRT2 is an NAD+-dependent deacetylase that belongs to the Sirtuin family, which consists of 7 members in humans(SIRT1-7). SIRT2 has been shown to deacetylate histone H3K18 in the immune response against bacterial infection[21] and, in turn, modulate the expression of anti-inflammatory genes. Glucocorticoid stimulation leads to the dissociation of the GR from Hsp[90] This allows GR to form homodimers and translocate to the nucleus, where it forms heterocomplex with NF-kB, preventing the transcriptional activation of inflammatory genes.[26]. Inhibition of Hsp[90] attenuates activation of NF-kB and inhibits expression of its downstream genes,[27,28] indicating a regulatory role for Hsp[90] in the NF-kB-dependent inflammatory response. Acetylated rat Hsp90α at K294 (Scroggins BT et al, but site corresponds to K295 in new version of rat Hsp90α: NP_786937) promotes its binding to its interacting partners[30]; we speculated that SIRT2 may repress immune reaction via Hsp90-GR signalling. Our results provide new insights into the regulation of the inflammation via SIRT2

| MATERIALS AND METHODS

Findings

| DISCUSSION