TY - JOUR
T1 - Longevity-relevant regulation of autophagy at the level of the acetylproteome
AU - Mariño, Guillermo
AU - Morselli, Eugenia
AU - Bennetzen, Martin V.
AU - Eisenberg, Tobias
AU - Megalou, Evgenia
AU - Schroeder, Sabrina
AU - Cabrera, Sandra
AU - Bénit, Paule
AU - Rustin, Pierre
AU - Criollo, Alfredo
AU - Kepp, Oliver
AU - Galluzzi, Lorenzo
AU - Shen, Si
AU - Malik, Shoaib A.
AU - Maiuri, Maria Chiara
AU - Horio, Yoshiyuki
AU - López-Otín, Carlos
AU - Andersen, Jens S.
AU - Tavernarakis, Nektarios
AU - Madeo, Frank
AU - Kroemer, Guido
N1 - Funding Information:
thus marking the proteins of control cells, resveratrol-treated cells and spermidine-treated cells with three distinct stable isotopes. Then, the three cultures were mixed and lysed simultaneously, followed by subcellular fractionation (to separate the cytoplasm and nuclei), purification of the proteins/peptides containing acetylated lysine residues and their identification by quantitative mass spectrometry (Fig. 1A). This experimental design allowed for the comparative quantification of the acet-ylproteome and its modifications by resveratrol and spermidine. We found that resveratrol or spermidine provoke altera-of enzymatic activities, the composition of and spermidine (a polyamine), induce tions (>1.2 fold) in the acetylation of 560 multiprotein complexes and their subcel-autophagy and increase longevity and lysine-containing motifs from 375 distinct lular localization/organization. these two effects are indeed linked by a proteins. Importantly, 170 proteins whose Two structurally unrelated pharmaco-cause-effect relationship. Thus, autophagy-acetylation status is modified in response logical agents, resveratrol (a polyphenol) incompetent strains of yeast (S. cerevisiae) to resveratrol or spermidine treatment overlap with proteins from the recently are able to induce autophagy in cytoplasts acetylproteome, as they are likewise mod-elucidated entire human autophagy pro-(enucleated cells) suggests that nuclear ulated by the nutritional status, as putative tein network consisting of 2,540 distinct acetylation reactions are dispensable for biomarkers of autophagy and longevity in intracellular proteins (Fig. 1B). spermidine and/or resveratrol-dependent humans. Both resveratrol and spermidine tended autophagy induction and that (de)acety- to induce the convergent (de)acetylation lation of critical cytoplasmic proteins of the same proteins. No major differences mediates the pro-autophagic activity of G.K. is supported by the Ligue Nationale were detected in the consensus (de)acety-spermidine and resveratrol. Collectively, contre le Cancer (Equipes labellisée), lation sites that were modified in response these results not only illustrate the differ-Agence Nationale pour la Recherche to resveratrol as compared to those ences between quiescent and proliferating (ANR), European Commission (Active affected by spermidine. In the nucleus, cells in terms of autophagy modulation, p53, Apo-Sys, ChemoRes, ApopTrain), resveratrol and spermidine mostly trigger but also suggest that after a fast and Fondation pour la Recherche Médicale convergent acetylation reactions. In the nuclear-independent autophagic response, (FRM), Institut National du Cancer cytosol, by contrast, both agents provoke transcriptional reprogramming is required (INCa), Cancéropôle Ile-de-France and both convergent acetylation and conver-to maintain an increased basal autophagic the AXA Chair for Longevity Research. gent deacetylation of multiple proteins activity, thus contributing to the previ-N.T. is supported by grants from the to a similar extent, although the number ously reported life-span extension. European Union Marie Curie actions of convergently deacetylated proteins is Taken together, all these observations and the European Research Council higher. We have recently reported that suggest that multiple post-translational (ERC), T.B. and F.M. are grateful to essential autophagy genes are required modifications of the acetylproteome can the European Commission for Grant for life-span extension due to spermidine likely regulate autophagy. Considering “APO-SYS”. M.V.B. is supported by the during conditions of chronological aging. that energy metabolism might influence Danish Ministry of Science, Technology This observed longevity increase is linked the acetylproteome both via an increase and Innovation (the EliteResearch initia-
PY - 2011/6
Y1 - 2011/6
N2 - The acetylase inhibitor, spermidine and the deacetylase activator, resveratrol, both induce autophagy and prolong life span of the model organism Caenorhabditis elegans in an autophagydependent fashion. Based on these premises, we investigated the differences and similarities in spermidine and resveratrol-induced autophagy. The deacetylase sirtuin 1 (SIRT1) and its orthologs are required for the autophagy induction by resveratrol but dispensable for autophagy stimulation by spermidine in human cells, Saccharomyces cerevisiae and C. elegans. SIRT1 is also dispensable for life-span extension by spermidine. Mass spectrometry analysis of the human acetylproteome revealed that resveratrol and/ or spermidine induce changes in the acetylation of 560 peptides corresponding to 375 different proteins. Among these, 170 proteins are part of the recently elucidated human autophagy protein network. Importantly, spermidine and resveratrol frequently affect the acetylation pattern in a similar fashion. In the cytoplasm, spermidine and resveratrol induce convergent protein de-acetylation more frequently than convergent acetylation, while in the nucleus, acetylation is dominantly triggered by both agents. We surmise that subtle and concerted alterations in the acetylproteome regulate autophagy at multiple levels.
AB - The acetylase inhibitor, spermidine and the deacetylase activator, resveratrol, both induce autophagy and prolong life span of the model organism Caenorhabditis elegans in an autophagydependent fashion. Based on these premises, we investigated the differences and similarities in spermidine and resveratrol-induced autophagy. The deacetylase sirtuin 1 (SIRT1) and its orthologs are required for the autophagy induction by resveratrol but dispensable for autophagy stimulation by spermidine in human cells, Saccharomyces cerevisiae and C. elegans. SIRT1 is also dispensable for life-span extension by spermidine. Mass spectrometry analysis of the human acetylproteome revealed that resveratrol and/ or spermidine induce changes in the acetylation of 560 peptides corresponding to 375 different proteins. Among these, 170 proteins are part of the recently elucidated human autophagy protein network. Importantly, spermidine and resveratrol frequently affect the acetylation pattern in a similar fashion. In the cytoplasm, spermidine and resveratrol induce convergent protein de-acetylation more frequently than convergent acetylation, while in the nucleus, acetylation is dominantly triggered by both agents. We surmise that subtle and concerted alterations in the acetylproteome regulate autophagy at multiple levels.
KW - Aging
KW - Caenorhabditis elegans
KW - Cancer
KW - HCT116
KW - SILAC
KW - Saccharomyces cerevisiae
UR - http://www.scopus.com/inward/record.url?scp=79957879876&partnerID=8YFLogxK
U2 - 10.4161/auto.7.6.15191
DO - 10.4161/auto.7.6.15191
M3 - Short survey
AN - SCOPUS:79957879876
SN - 1554-8627
VL - 7
SP - 647
EP - 649
JO - Autophagy
JF - Autophagy
IS - 6
ER -
