Pro-autophagic polyphenols reduce the acetylation of cytoplasmic proteins

Resveratrol is a polyphenol contained in red wine that has been amply investigated for its benefcial efects 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 benefcial efect 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 afecting the acetylation levels of cellular proteins. phenolic compounds found in red wine, including anthocyanins (oenin), stilbenoids (piceatannol), monophenols (cafeic acid, gallic acid) glucosides (delphinidin, kuronamin, peonidin) and favonoids (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 immunofuorescence 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-efect relationship between the deacetylation of cytoplasmic proteins and autophagy induction by red wine components.