Pro-autophagic polyphenols reduce the acetylation of cytoplasmic proteins.
Resveratrol is a polyphenol contained in red wine that has been amply investigated for its beneficial effects on organismal metabolism, in particular in the context of the so-called "French paradox," i.e., the relatively low incidence of coronary heart disease exhibited by a population with a high dietary intake of cholesterol and saturated fats. At least part of the beneficial effect of resveratrol on human health stems from its capacity to promote autophagy by activating the NAD-dependent deacetylase sirtuin 1. However, the concentration of resveratrol found in red wine is excessively low to account alone for the French paradox. Here, we investigated the possibility that other mono- and polyphenols contained in red wine might induce autophagy while affecting the acetylation levels of cellular proteins. Phenolic compounds found in red wine, including anthocyanins (oenin), stilbenoids (piceatannol), monophenols (caffeic acid, gallic acid) glucosides (delphinidin, kuronamin, peonidin) and flavonoids (catechin, epicatechin, quercetin, myricetin), were all capable of stimulating autophagy, although with dissimilar potencies. Importantly, a robust negative correlation could be established between autophagy induction and the acetylation levels of cytoplasmic proteins, as determined by a novel immunofluorescence staining protocol that allows for the exclusion of nuclear components from the analysis. Inhibition of sirtuin 1 by both pharmacological and genetic means abolished protein deacetylation and autophagy as stimulated by resveratrol, but not by piceatannol, indicating that these compounds act through distinct molecular pathways. In support of this notion, resveratrol and piceatannol synergized in inducing autophagy as well as in promoting cytoplasmic protein deacetylation. Our results highlight a cause-effect relationship between the deacetylation of cytoplasmic proteins and autophagy induction by red wine components.
INSERM, U848, Villejuif, France.
Federico
F
Pietrocola
Guillermo
G
Mariño
Delphine
D
Lissa
Erika
E
Vacchelli
Shoaib Ahmad
SA
Malik
Mireia
M
Niso-Santano
Naoufal
N
Zamzami
Lorenzo
L
Galluzzi
Maria Chiara
MC
Maiuri
Guido
G
Kroemer
D000107:Acetylation; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008856:Microscopy, Fluorescence; D059808:Polyphenols / Q000494:pharmacology*; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
D059808:Polyphenols; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol