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

J Cell Mol Med. 2020 Jul;24(13):7439-7450. doi: 10.1111/jcmm.15365. Epub 2020 Jun 9.

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.

Keywords: Glucocorticoid receptor; Hsp90; SIRT2; deacetylation; inflammatory cytokine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Escherichia coli / metabolism
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Inflammation / metabolism*
  • Lipopolysaccharides / pharmacology
  • Models, Biological
  • Protein Binding / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Rats
  • Receptors, Glucocorticoid / metabolism*
  • Signal Transduction* / drug effects
  • Sirtuin 2 / chemistry
  • Sirtuin 2 / metabolism*
  • Solubility

Substances

  • HSP90 Heat-Shock Proteins
  • Lipopolysaccharides
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Glucocorticoid
  • Sirtuin 2