title: Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome.
abstract: Autophagy protects organelles, cells, and organisms against several stress conditions. Induction of autophagy by resveratrol requires the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1). In this paper, we show that the acetylase inhibitor spermidine stimulates autophagy independent of SIRT1 in human and yeast cells as well as in nematodes. Although resveratrol and spermidine ignite autophagy through distinct mechanisms, these compounds stimulate convergent pathways that culminate in concordant modifications of the acetylproteome. Both agents favor convergent deacetylation and acetylation reactions in the cytosol and in the nucleus, respectively. Both resveratrol and spermidine were able to induce autophagy in cytoplasts (enucleated cells). Moreover, a cytoplasm-restricted mutant of SIRT1 could stimulate autophagy, suggesting that cytoplasmic deacetylation reactions dictate the autophagic cascade. At doses at which neither resveratrol nor spermidine stimulated autophagy alone, these agents synergistically induced autophagy. Altogether, these data underscore the importance of an autophagy regulatory network of antagonistic deacetylases and acetylases that can be pharmacologically manipulated.
authors.affiliation: Institut National de la Santé et de la Recherche Medicale U848, Villejuif, France.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Morselli
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mariño
authors.forename: Martin V
authors.initials: MV
authors.lastname: Bennetzen
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.forename: Evgenia
authors.initials: E
authors.lastname: Megalou
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schroeder
authors.forename: Sandra
authors.initials: S
authors.lastname: Cabrera
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Alfredo
authors.initials: A
authors.lastname: Criollo
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Shensi
authors.initials: S
authors.lastname: Shen
authors.forename: Shoaib Ahmad
authors.initials: SA
authors.lastname: Malik
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Maiuri
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Horio
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Jens S
authors.initials: JS
authors.lastname: Andersen
authors.forename: Nektarios
authors.initials: N
authors.lastname: Tavernarakis
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000115:Acetylesterase / Q000037:antagonists & inhibitors; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D020543:Proteome / Q000187:drug effects; D000077185:Resveratrol; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013095:Spermidine / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D020543:Proteome; D013267:Stilbenes; D000115:Acetylesterase; D056564:Sirtuin 1; D000077185:Resveratrol; D013095:Spermidine