SIRT7 regulates the nuclear export of NF-κB p65 by deacetylating Ran

Biochim Biophys Acta Mol Cell Res. 2019 Sep;1866(9):1355-1367. doi: 10.1016/j.bbamcr.2019.05.001. Epub 2019 May 7.

Abstract

Sirtuin 7 (SIRT7) is an NAD+-dependent lysine deacetylase that regulates diverse biological processes. We recently observed that SIRT7 deficiency suppresses the nuclear accumulation of p65, which is a component of nuclear factor kappa B. However, the underlying molecular mechanism remains elusive. In this study, we demonstrated that SIRT7 interacts with a small GTPase, Ras-related nuclear antigen (Ran), and deacetylates Ran at K37. The nuclear export of p65 was facilitated in SIRT7-deficient fibroblast cells, while the nuclear export was inhibited in SIRT7-deficient cells expressing K37R-Ran (deacetylation-mimicking mutant). Additionally, the nuclear export of p65 in wild-type fibroblast cells was promoted by K37Q-Ran (acetylation-mimicking mutant). K37Q-Ran exhibited an increased ability to bind to chromosome region maintenance 1 (CRM1), which is a major nuclear receptor that mediates the export of cargo proteins, and enhanced the binding between p65 and CRM1. These data suggest that SIRT7 is a lysine deacetylase that targets the K37 residue of Ran to suppress the nuclear export of p65.

Keywords: Deacetylation; Exportin; Inhibitor of NF-κB (IκB); Nuclear export; Nuclear factor kappa B (NF-κB); SIRT7; p65.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Active Transport, Cell Nucleus / physiology*
  • Animals
  • Fatty Acids, Unsaturated / pharmacology
  • Fibroblasts / drug effects
  • GTP Phosphohydrolases
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Karyopherins / metabolism
  • Mice
  • Mice, Knockout
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Transcription Factor RelA / metabolism*

Substances

  • Fatty Acids, Unsaturated
  • Karyopherins
  • Receptors, Cytoplasmic and Nuclear
  • SIRT7 protein, human
  • Transcription Factor RelA
  • exportin 1 protein
  • Sirtuins
  • GTP Phosphohydrolases
  • leptomycin B