Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65

Abstract

Inflammation increases the abundance of inducible nitric oxide synthase (iNOS), leading to enhanced production of nitric oxide (NO), which can modify proteins by S-nitrosylation. Enhanced NO production increases the activities of the transcription factors p53 and nuclear factor κB (NF-κB) in several models of disease-associated inflammation. S-Nitrosylation inhibits the activity of the protein deacetylase SIRT1. SIRT1 limits apoptosis and inflammation by deacetylating p53 and p65 (also known as RelA), a subunit of NF-κB. We showed in multiple cultured mammalian cell lines that NO donors or inflammatory stimuli induced S-nitrosylation of SIRT1 within CXXC motifs, which inhibited SIRT1 by disrupting its ability to bind zinc. Inhibition of SIRT1 reduced deacetylation and promoted activation of p53 and p65, leading to apoptosis and increased expression of proinflammatory genes. In rodent models of systemic inflammation, Parkinson’s disease, or aging-related muscular atrophy, S-nitrosylation of SIRT1 correlated with increased acetylation of p53 and p65 and activation of p53 and NF-κB target genes, suggesting that S-nitrosylation of SIRT1 may represent a proinflammatory switch common to many diseases and aging.

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…While increases in oxidative stress favor productive viral replication, antioxidant defenses favor the development and maintenance of latency (106)(107)(108). Under this model, inflammatory stimuli increase the activity of the transcriptional activators NF-κB and NFAT, which are required for the transcription of viral genes (109, 110) and p53, which coincidently mediates apoptosis (111). Antioxidants may therefore silence transcriptional activity (109,110), while pro-oxidants, such as arsenic trioxide, may reactivate the viral reservoir (112).…”

Mechanism of Sirt1 NAD+-dependent Protein Deacetylase Inhibition by Cysteine S-Nitrosation

“…Recent work has implicated oxidative post-translational modification of cysteine residues within Sirt1 as a mechanism of physiological inhibition (4 -11). In particular, S-nitrosation of Sirt1 was recently suggested to inhibit Sirt1 deacetylase activity, resulting in increased acetylation of Sirt1 deacetylase substrates PGC1-␣, p53, and the p65 subunit of NF-B (4,5). An increase in S-nitrosation of Sirt1 was also suggested to occur in the context of aging and to correspond to decreased Sirt1 deacetylation of cellular targets (5).…”

“…In particular, S-nitrosation of Sirt1 was recently suggested to inhibit Sirt1 deacetylase activity, resulting in increased acetylation of Sirt1 deacetylase substrates PGC1-␣, p53, and the p65 subunit of NF-B (4,5). An increase in S-nitrosation of Sirt1 was also suggested to occur in the context of aging and to correspond to decreased Sirt1 deacetylation of cellular targets (5). However, in this study (5) endogenous nitric oxide (NO) was generated through lipopolysaccharide and cytokine treatment to induce inducible nitric-oxide synthase (iNOS) 3 expression, conditions known to also stimulate production of hydrogen peroxide by NADPH oxidases (12).…”

“…An increase in S-nitrosation of Sirt1 was also suggested to occur in the context of aging and to correspond to decreased Sirt1 deacetylation of cellular targets (5). However, in this study (5) endogenous nitric oxide (NO) was generated through lipopolysaccharide and cytokine treatment to induce inducible nitric-oxide synthase (iNOS) 3 expression, conditions known to also stimulate production of hydrogen peroxide by NADPH oxidases (12). Therefore, cysteine sulfenylation could also have contributed to the observed Sirt1 cysteine oxidation.…”

An Agonist of the Protective Factor SIRT1 Improves Functional Recovery and Promotes Neuronal Survival by Attenuating Inflammation after Spinal Cord Injury

“…SIRT1 has been shown to play a critical role in regulating various metabolic and pathophysiological processes, such as inflammation, apoptosis, stress resistance, differentiation, and aging (Bordone and Guarente, 2005;He et al, 2010;Busch et al, 2012;Lim et al, 2012;Xie et al, 2013;Shinozaki et al, 2014). In addition, SIRT1 is directly implicated in the modulation of inflammatory responses by deacetylation of histones and critical transcription factors, such as nuclear factor B, resulting in the transcriptional repression of various genes related to inflammation (Yeung et al, 2004;Kauppinen et al, 2013).…”