The Human Sir2 Ortholog, SIRT2, Is an NAD+-Dependent Tubulin Deacetylase

Abstract

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.

Class II histone deacetylases: versatile regulators

“…The dependency of class III enzymes on NAD þ could also link the activity of the complex to the metabolic status of the cell. A similar combination of class II and class III enzymes in a multiprotein complex was recently observed for HDAC6 and SIRT2, a human class III HDAC [56]. SMRTand N-CoR interact both with class IIa HDACs and with HDAC3 through distinct domains [52,53,57,58], an observation that explains why class IIa HDACs coimmunoprecipitate with HDAC3 [5,16,48].…”

“…HDAC6 overexpression promotes chemotactic cell movement, a cellular function dependent on microtubules. We have independently observed that SIRT2, a NAD þ -dependent class III HDAC, deacetylates lysine 40 of a-tubulin both in vitro and in vivo [56]. Both HDAC6 and SIRT2 interact and co-localize in the cytoplasm with the microtubule network (Fig.…”

“…Both HDAC6 and SIRT2 interact and co-localize in the cytoplasm with the microtubule network (Fig. 4) [56]. Suppression of either HDAC6 or SIRT2 mediated by siRNA leads to a relative hyperacetylation of a-tubulin acetylation in vivo [56,87,88].…”

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

“…2003), we previously showed the enrichment of Sirt2 protein on the meiotic apparatus—the spindle and midbody during oocyte maturation (Zhang et al., 2014). In support of this observation, we here confirmed that Sirt2 knockdown in mouse oocytes results in spindle defects and chromosome disorganization, with impaired K‐MT attachment.…”

“…For example, histone H4K16 and α‐tubulin‐K40 have been indicated as the potential targets of Sirt2 to modulate chromatin conformation and microtubule stability (North et al., 2003; Vaquero et al., 2006). Sirt2 participates in myelin formation of Schwann cells by deacetylating partitioning defective 3 homologue (PAR3) (Beirowski et al., 2011).…”