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

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

Author information

1
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
2
Department of Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
3
Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki-shi, Osaka 567-0085, Japan.
4
Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: k-yamaga@kumamoto-u.ac.jp.

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

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