Acetylation of Yeast AMPK Controls Intrinsic Aging Independently of Caloric Restriction

SummaryAcetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory β subunit of the Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), and ultimately leading to slower growth but extended replicative life span. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a protein acetylation-phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging, and extends replicative life span in yeast.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (213 K)Download as PowerPoint slideHighlights► The yeast AMPK β subunit Sip2 is acetylated by NuA4 and deacetylated by Rpd3 ► Sip2 acetylation decreases with age, and increasing Sip2 acetylation extends life span ► Acetylated Sip2 binds and inhibits Snf1, reducing Sch9 phosphorylation ► The anti-aging effect of Sip2 acetylation is independent of nutrition and TORC activity