SIRT2 regulates NF-κB-dependent gene expression through deacetylation of p65 Lys310

Abstract

SummaryNF-kB regulates the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation and survival. In this study, we identified SIRT2 as a deacetylase of the transcription factor p65. SIRT2 is a member of the family of sirtuins, which are NAD + -dependent deacetylases involved in several cellular processes. SIRT2 interacts with p65 in the cytoplasm and deacetylates p65 in vitro and in vivo at Lys310. Moreover, p65 is hyperacetylated at Lys310 in Sirt2 -/-cells after TNFa stimulation, which results in the increase in expression of a subset of p65 acetylation-dependent target genes. Our work provides evidence that p65 is deacetylated by SIRT2 in the cytoplasm to regulate the expression of specific NF-kBdependent genes.

Calorie restriction and sirtuins revisited

“…p65 of this transcription factor is deacetylated and repressed by SIRT1 (Yeung et al 2004) and SIRT2 (Rothgiesser et al 2010), and histones at NFkB-regulated genes are deacetylated by SIRT6 (Kawahara et al 2009) to reinforce repression. These sirtuin functions may help explain the global anti-inflammatory effect of CR, which may be an important mechanism by which this diet slows aging.…”

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

“…7 SIRT2 also deacetylates α-tubulin, 6,8 suggesting a function in cytoskeletal organization. In addition to targeting α-tubulin, SIRT2 is known to specifically target NFkB, 9 FOXO transcription factors [10][11][12] and p53. [13][14][15] The AKT pathway is frequently activated in acute myeloid leukemia (AML).…”

Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

“…Sirt2, the primary cytoplasmic sirtuin, has been attributed tumor suppressor functions and a role in maintaining genome integrity as well as a role in programmed necrosis (20 -22). Among its deacetylation targets are FoxO transcription factors, tubulin, keratin 8, eIF5A, APC/C, and NF-B-p65 (23)(24)(25)(26)(27)(28)(29). Controversy remains, however, regarding the role of Sirt2 in regulating tubulin acetylation in the brain (30).…”