Acetylation of yeast AMPK controls intrinsic aging independently of caloric restriction

Jin Ying Lu, Yu Yi Lin, Jin Chuan Sheu, June Tai Wu, Fang Jen Lee, Yue Chen, Min I. Lin, Fu Tien Chiang, Tong Yuan Tai, Shelley L. Berger, Yingming Zhao, Keh Sung Tsai, Heng Zhu, Lee Ming Chuang, Jef D. Boeke

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)969-979
Number of pages11
JournalCell
Volume146
Issue number6
DOIs
StatePublished - Sep 16 2011

Bibliographical note

Funding Information:
We thank Sheng-Ce Tao and Chien-Sheng Chen for their early contribution to this work. We are grateful to Dr. Brian K. Kennedy for providing sch9Δ strain, Dr. Robbie Loewith for providing SCH9 phosphorylation mutants, and Dr. Marian B. Carlson for providing snf1-K84R construct. We thank Dr. Fang-Jen Lee for kindly sharing the laboratory space and reagents. We thank Department of Medical Science, National Taiwan University for technical help with sequencing. We thank Dr. Yi-Juang Chern for critical suggestions on this work. Work was supported by National Science Council (NSC 98-2314-B-002-031-MY3 to J.-Y.L.), National Taiwan University Hospital (099-001376, to J.-Y.L.), National Taiwan University (99C101-603 to J.-Y.L., Y.-Y.L., and L.-M.C.), Liver Disease Prevention & Treatment Research Foundation (Taiwan) (to J.-Y.L. and Y.-Y.L.), and NIH Common Fund grant (USA) (U54-RR020839 to H.Z. and J.D.B.).

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