Redox regulation of SIRT1 in inflammation and cellular senescence

Abstract

Sirtuin 1 (SIRT1) regulates inflammation, aging (life span and health span), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. SIRT1 level and activity are decreased in chronic inflammatory conditions and aging, in which oxidative stress occurs. SIRT1 is regulated by a NAD(+)-dependent DNA repair enzyme, poly(ADP-ribose) polymerase-1 (PARP1), and subsequent NAD(+) depletion by oxidative stress may have consequent effects on inflammatory and stress responses as well as cellular senescence. SIRT1 has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to posttranslational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65, and FOXO3, thereby enhancing the inflammatory, prosenescent, and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox posttranslational modifications of SIRT1 and its roles in PARP1 and NF-κB activation, and FOXO3 and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging, are discussed. Furthermore, we have also discussed various novel ways to activate SIRT1 either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases.

Keywords: COPD; FOXO3; Free radicals; GSH; Inflammation; NF-κB; Oxidants; Redox signaling; SIRT1; Senescence; Tobacco smoke.

Figure 1. Schematic of SIRT1 residues for post-translational modifications

Mammalian SIRT1 comprises 747 amino acids, which contains a central catalytic domain (green), two nuclear localization sequences (NLS, blue), and two nuclear export sequences (NES, red). P: phosphorylation, GSH: S-glutathionylation, SNO: S-nitrosylation, CO: carbonylation, SUMO: SUMOylation, Ser: serine, Cys: cysteine, aa: amino acids, Thr: threonine, Lys: lysine. N: N-terminal end, and C: C-terminal end.

Figure 2. Post-translational modifications of SIRT1

In response to oxidative stress, SIRT1 undergoes post-translational modifications, such as phosphorylation (P), S-nitrosylation (SNO), S-glutathionylation (GSH), carbonylation (CO), and SUMOylation (SUMO). SIRT1 deacetylase activity and subsequent cellular responses are affected by these post-translational modifications. Alteration in intracellular GSH/GSSG ratio by oxidative stress can also affect these modifications.

Figure 3. Transcriptional regulation of SIRT1 in response to oxidative stress

Transcription of SIRT1 is repressed by activation of p53, HIC1, and E2F1 in response to oxidative stress. FOXO3 removes p53 from two p53-binding sites on the SIRT1 promoter. Repression of SIRT1 transcription by p53 may reduce the activation of endothelial nitric oxide synthase (eNOS) through eNOS acetylation. SIRT1 also deacetylates p53 and FOXO3, and in turn modulates their transcriptional activity.

Figure 4. Translational regulation of SIRT1 stability in response to oxidative stress

The Hu antigen R (HuR) plays a critical role in stability of SIRT1 mRNA. Under oxidative stress, HuR-SIRT1 mRNA complex is rapidly dissociated, leading to reduction of SIRT1 mRNA stability.

Figure 5. Regulation of SIRT1 nucleocytoplasmic shuttling by oxidative stress

Oxidative stress causes oxidative and carbonyl modifications as well as nucleocytoplasmic shuttling of SIRT1 to the cytoplasm. This will decrease SIRT1 protein levels through proteasomal degradation in the cytoplasm. At the same time, the transcription of NF-κB-dependent pro-inflammatory genes is increased once SIRT1 is reduced. Intracellular redox status (i.e., GSH/GSSG ratio) can also affect nucleocytoplasmic shuttling of SIRT1. NES, Nuclear export sequences.

Figure 6. SIRT1 in regulating inflammation and cellular senescence under oxidative stress

Oxidants derived from cigarette smoke inhibit SIRT1 activity, and reduce its levels by post-translational modifications. SIRT1 reduction leads to RelA/p65 and FOXO3 acetylation, as well as modifications of histones H3 and H4. The acetylation of these molecules by SIRT1 reduction causes the abnormal transcription of pro-inflammatory, antioxidant, pro-senescent and pro-apoptotic genes involved in oxidative stress, inflammation, and premature cellular senescence.

Figure 7. Interplay between SIRT1 and PARP1 under oxidative stress

Oxidative or genotoxic stress and abnormal redox status activate PARP1, leading to the depletion of NAD⁺ and subsequent inactivation of SIRT1 deacetylase activity. PARP1 activation is also regulated by intracellular levels of GSH/GSSG. Furthermore, SIRT1 regulates PARP1 activity via deacetylating PARP1 in response to oxidative stress. NMN: nicotinamide mononucleotide, NAMPT: nicotinamide phosphoribosyltransferase, NMNAT: nicotinamide/nicotinic acid mononucleotide adenylyltransferase, PARP1: poly (ADP-ribose) polymerase-1.

Figure 8. SIRT1-mediated regulation of eNOS

Oxidant/carbonyl stress down-regulates the SIRT1 activity and level. This will regulate PARP1, and cause acetylation of CAV-1 and eNOS, which influences several cellular processes, such as apoptosis, angiogenesis and vascular homeostasis in endothelial cells. PARP1: poly (ADP-ribose) polymerase-1, CAV-1: caveolin-1: eNOS: endothelial nitric oxide synthase, Ac: acetylation.