Redox Regulation of Sirtuin-1 by S-Glutathiolation

Abstract

Sirtuin-1 (SIRT1) is an NAD(+)-dependent protein deacetylase that is sensitive to oxidative signals. Our purpose was to determine whether SIRT1 activity is sensitive to the low molecular weight nitrosothiol, S-nitrosoglutathione (GSNO), which can transduce oxidative signals into physiological responses. SIRT1 formed mixed disulfides with GSNO-Sepharose, and mass spectrometry identified several cysteines that are modified by GSNO, including Cys-67 which was S-glutathiolated. GSNO had no effect on basal SIRT1 deacetylase activity, but inhibited stimulation of activity by resveratrol (RSV) with an IC(50) of 69 microM. These observations indicate that S-glutathiolation of SIRT1 by low concentrations of reactive glutathione can modulate its enzymatic activity.

Stem cells and the impact of ROS signaling

“…Oxidation of Cys in PTEN catalytic sites causes inactivation (Lee et al, 2002) Modulation of the PI3K/AKT pathway PTEN inactivation by NOX-generated ROS increases PI3K-AKT activation in NSCs (Le Belle et al, 2011) Sirtuins (SIRTs) Cys oxidation inhibits SIRT1 activity (Zee et al, 2010) SIRTs are NAD + -dependent deacetylases that modulates the activity of FOXO TFs (Brunet et al, 2004;Kobayashi et al, 2005;Daitoku et al, 2004;Motta et al, 2004;van der Horst et al, 2004) SIRT3 controls ROS levels during HSC ageing (Brown et al, 2013) FOXOs possess 5-10 reactive Cys; the FOXO4 signaling switch from cell cycle arrest to apoptosis is redox mediated (direct); redox modulation of PTEN and AKT impact FOXOs negatively or positively, respectively (indirect) (Dansen et al, 2009) Can regulate the transcription of antioxidant enzymes, such as SOD2, catalase and GPX1…”

Glutaredoxin-1 Up-regulation Induces Soluble Vascular Endothelial Growth Factor Receptor 1, Attenuating Post-ischemia Limb Revascularization

“…GSH adducts may provide signaling mechanism and protect proteins from irreversible oxidation during fluctuations of reactive oxygen and nitrogen species levels (1). This reversible modification can result in functional inhibition (2)(3)(4) or activation (5, 6) of a broad range of proteins with redox-sensitive thiols. Thus, regulation of GSH adducts has significance in various clinical conditions (7).…”

SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD

“…SIRT1; cigarette smoke; MMPs; TIMPs; emphysema; COPD SIRTUIN1 (SIRT1), a type III histone/protein deacetylase, plays an important role in inflammation, stress resistance, and cellular senescence/aging through the deacetylation of histones, transcription factors, and signaling molecules. It is a redoxsensitive deacetylase that can be posttranslationally modified by oxidants and carbonyl stress, leading to proteasomal degradation (9,36,59). This may be one of the reasons for the reduction of SIRT1 level in peripheral lung tissues of smokers and patients with chronic obstructive pulmonary disease (COPD)/emphysema (36, 55).…”

“…It is a redoxsensitive deacetylase that can be posttranslationally modified by oxidants and carbonyl stress, leading to proteasomal degradation (9,36,59). This may be one of the reasons for the reduction of SIRT1 level in peripheral lung tissues of smokers and patients with chronic obstructive pulmonary disease (COPD)/emphysema (36,55).…”