Journal
CELL
Volume 146, Issue 6, Pages 968-978Publisher
CELL PRESS
DOI: 10.1016/j.cell.2011.07.044
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Funding
- National Science Council (NSC) [98-2314-B-002-031-MY3]
- National Taiwan University Hospital [099-001376]
- National Taiwan University [99C101-603]
- Liver Disease Prevention & Treatment Research Foundation (Taiwan)
- NIH (USA) [U54-RR020839]
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Acetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory beta 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.
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