title: Spermidine induces autophagy by inhibiting the acetyltransferase EP300.
abstract: Several natural compounds found in health-related food items can inhibit acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(α)-acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors.
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Pietrocola
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Lachkar
authors.affiliation: Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, Villejuif 94805, France.
authors.forename: D P
authors.initials: DP
authors.lastname: Enot
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Niso-Santano
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Bravo-San Pedro
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Sica
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Izzo
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Maiuri
authors.affiliation: 1] Institute of Molecular Biosciences, University of Graz, Graz 8010, Austria [2] BioTechMed Graz, Graz 8010, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Madeo
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Mariño
authors.affiliation: 1] Equipe 11 labellisée par la Ligue Nationale contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris 75006, France [2] Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, Villejuif 94805, France [4] Université de Paris Sud, Villejuif 94805, France [5] Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris 75015, France.
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D013095:Spermidine / Q000494:pharmacology*
chemical_list: D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D013095:Spermidine