Reversible glutathionylation of Sir2 by monothiol glutaredoxins Grx3/4 regulates stress resistance
Reverter Branchat, Gemma
MetadataShow full item record
The regulatory mechanisms of yeast Sir2, the founding member of the sirtuin family involved in oxidative stress and aging, are unknown. Redox signaling controls many cellular functions, especially under stress situations, with dithiol glutaredoxins (Grxs) playing an important role. However, monothiol Grxs are not considered to have major oxidoreductase activity. The present study investigated the redox regulation of yeast Sir2, together with the role and physiological impact of monothiol Grx3/4 as Sir2 thiol-reductases upon stress. S-glutathionylation of Sir2 upon disulfide stress was demonstrated both in vitro and in vivo, and decreased Sir2 deacetylase activity. Physiological levels of nuclear Grx3/4 can reverse the observed post-translational modification. Grx3/4 interacted with Sir2 and reduced it after stress, thereby restoring telomeric silencing activity. Using site-directed mutagenesis, key cysteine residues at the catalytic domain of Sir2 were identified as a target of S-glutathionylation. Mutation of these residues resulted in cells with increased resistance to disulfide stress. We provide new mechanistic insights into Grx3/4 regulation of Sir2 by S-deglutathionylation to increase cell resistance to stress. This finding offers news perspectives on monothiol Grxs in redox signaling, describing Sir2 as a physiological substrate regulated by S-glutathionylation. These results might have a relevant role in understanding aging and age-related diseases.
Is part ofFree Radical Biology and Medicine, 2016, vol. 96, p. 45-56
European research projects
- Articles publicats (IRBLleida) 
- Articles publicats (Ciències Mèdiques Bàsiques) 
- Publicacions de projectes de recerca del Plan Nacional 
- Articles publicats (Medicina Experimental) 
- Articles publicats (Grup de Recerca en Estrès Cel·lular i Supervivència en Models Eucariotes) 
Showing items related by title, author, creator and subject.
The FOX transcription factor Hcm1 regulates oxidative metabolism in response to early nutrient limitation in yeast. Role of Snf1 and Tor1/Sch9 kinases Rodríguez Colman, Maria José; Sorolla Bardají, Maria Alba; Vall-llaura Espinosa, Núria; Tamarit Sumalla, Jordi; Ros Salvador, Joaquim; Cabiscol Català, Elisa (Elsevier, 2013)Within Saccharomyces cerevisiae, Hcm1is a member of the forkhead transcription factor family with a role in chromosome organization. Our group recently described its involvement in mitochondrial biogenesis and stress ...
Vall-llaura Espinosa, Núria; Mir, Noèlia; Garrido, Lourdes; Vived Maza, Celia; Cabiscol Català, Elisa (Elsevier, 2019-06)Yeast Sir2 is an NAD-dependent histone deacetylase related to oxidative stress and aging. In a previous study, we showed that Sir2 is regulated by S-glutathionylation of key cysteine residues located at the catalytic domain. ...
Impaired PLP-dependent metabolism in brain samples from Huntington disease patients and transgenic R6/1 mice Sorolla Bardají, Maria Alba; Rodríguez Colman, Maria José; Vall-llaura Espinosa, Núria; Vived Maza, Celia; Fernández Nogales, Marta; Lucas, José J.; Ferrer, Isidre; Cabiscol Català, Elisa (Springer Science, Business Media, 2016-06)Oxidative stress has been described as important to Huntington disease (HD) progression. In a previous HD study, we identified several carbonylated proteins, including pyridoxal kinase and antiquitin, both of which are ...