Class IIa HDACs Are Signal Responsive Deacetylases

The potent repressive activity of class IIa HDACs on MEF2 dictates that these deacetylases must be subject to strict regulation to protect skeletal muscle. Studies in cultured cells showed that all class IIa HDAC members are regulated by phosphorylation and intracellular trafficking. Phosphorylation of several conserved serine residues in the N-terminus creates docking sites for the 14-3-3 protein (Fig. 2) (Grozinger and Schreiber 2000; Wang et al. 2000). Binding of 14-3-3 to HDAC4 and -5 causes their dissociation from MEF2 and exposes the nuclear export sequence (NES) for CRM1, leading to their nuclear export (Wang and Yang 2001). Cytoplasmic retention of HDAC4 and -5 releases nuclear MEF2 from their inhibitory effect (Miska et al. 1999; Zhao et al. 2001; Grozinger and Schreiber 2000). The most well-characterized kinase pathway that regulates class IIa HDAC phosphory-lation is via CaMK. The combined effects of CaMK-mediated phosphorylation on both MEF2 dissociation and HDAC nuclear export explains how CaMK stimulates MEF2 transcriptional activity and reverses the inhibitory effect of class IIa HDACs upon MEF2 (McKinsey et al. 2002; Wu et al. 2000; Naya et al. 1999).

However, not all class IIa HDACs share the same subcellular compartment under the identical cultured condition, revealing that their intracellular trafficking is regulated differently. For example, HDAC4 and -5, despite their extensive sequence homology, often display different subcellular localization patterns. In undifferentiated myoblasts, HDAC4 localizes predominately to the cytoplasm as a result of phosphorylation and 14-3-3-mediated nuclear export; however upon differentiation into myotubes, significant portions of HDAC4 accumulate in the nucleus (Zhao et al. 2001). The prominent nuclear translocation implies a regulatory function for HDAC4 in differentiated myofibers. In contrast, HDAC5 was reported to reside predominately in the nucleus of undifferentiated myoblasts but was exported to the cytoplasm upon differentiation, an observation consistent with an inhibitory role for HDAC5 in muscle differentiation (McKinsey et al. 2000). It should be noted that HDAC5 remains largely nuclear in terminally differentiated myotubes (Zhao et al. 2001). The biological significance of this differential localization of HDAC4 and HDAC5 is not yet understood but correlates with their differential affinity for CaMKII. HDAC4 but not HDAC5 is preferentially bound and phosphorylated by CaMKII (Backs et al. 2006). The differential affinity could underlie a more prominent activity of HDAC4 in skeletal muscle transcription remodeling (Cohen et al. 2007), a process thought to be regulated by CaMKII.

In addition to CaMKII, other kinases for class IIa HDACs have been identified and likely operate in response to different physiological cues. For example, AMP-activated kinase (AMPK), the critical sensor for intracellular metabolic state, can phosphorylate HDAC5 and lead to its nuclear export (McGee et al. 2009). An increase in AMP (energy deficiency) caused by exercise could activate AMPK, leading to HDAC5 phosphorylation and MEF2 activation. Even the regulation of HDAC4 phosphorylation in actively contracting and resting myofibers involves different kinases (Shen et al. 2006). When stimulated, HDAC4 nuclear efflux falls under the control of CaMKII; however, under resting conditions, CaMKII is unable to account for HDAC4 nuclear export (Shen et al. 2006). Instead, nuclear export under resting conditions is likely controlled by another kinase, such as PKD or PKC isoforms. It should be noted that other kinases have been implicated in phosphorylating class IIa HDACs including Mirk/dyrk1B and salt-inducible kinase (SIK) (Deng et al. 2005; Matthews et al. 2006; van der Linden et al. 2007). The physiological relevance of these phosphorylation events in skeletal muscle, in most cases, remains to be established. It is clear that despite their extensively shared biochemical activities, class IIa HDAC members are subject to differential regulation. The involvement of multiple kinases also indicates that HDAC4 and related deacetylases could integrate multiple signaling events and modify muscle properties accordingly.

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