The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.
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 alpha-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.
North
Brian J
BJ
Department of Physiology, University of California, San Francisco, 94141, San Francisco, CA, USA
Marshall
Brett L
BL
Borra
Margie T
MT
Denu
John M
JM
Verdin
Eric
E
D002460:Cell Line; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008870:Microtubules / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism; D056565:Sirtuin 2; D037761:Sirtuins / Q000378:metabolism*; D013379:Substrate Specificity; D014404:Tubulin / Q000378:metabolism
D011994:Recombinant Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D014404:Tubulin; D009243:NAD; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases