Molecular Cell, Volume 11, Issue 2 , February 2003, Pages 437-444.
Brian J. North (1)(3), Brett L. Marshall (3), Margie T. Borra (4), John M. Denu (4) and Eric Verdin (2)(3)
(1) Department of Physiology, University of California, San Francisco, San Francisco, CA 94141, USA
(2) Department of Medicine, University of California, San Francisco, San Francisco, CA 94141, USA
(3) Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94141, USA
(4) Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97201, USA
Received 7 May 2002; Revised 26 December 2002. Available online 6 March 2003.
The silent information regulator 2 protein (Sir2p) of Saccharomyces cerevisiae is an NAD-dependent histone deacetylase that plays a critical role in transcriptional silencing. Here, we report that a human ortholog of Sir2p, sirtuin type 2 (SIRT2), is a predominantly cytoplasmic protein that colocalizes with microtubules. SIRT2 deacetylates lysine-40 of -tubulin both in vitro and in vivo. Knockdown of SIRT2 via siRNA results in tubulin hyperacetylation. SIRT2 colocalizes and interacts in vivo with HDAC6, another tubulin deacetylase. Enzymatic analysis of recombinant SIRT2 in comparison to a yeast homolog of Sir2 protein (Hst2p) shows a striking preference of SIRT2 for acetylated tubulin peptide as a substrate relative to acetylated histone H3 peptide. These observations establish SIRT2 as a bona fide tubulin deacetylase.