Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5

Abstract

Skeletal muscle differentiation is controlled by interactions between myocyte enhancer factor-2 (MEF2) and myogenic basic helix-loop-helix transcription factors. Association of MEF2 with histone deacetylases (HDAC) -4 and -5 results in repression of MEF2 target genes and inhibition of myogenesis. Calcium͞calmodulin-dependent protein kinase (CaMK) signaling promotes myogenesis by disrupting MEF2-HDAC complexes and stimulating HDAC nuclear export. To further define the mechanisms that confer CaMK responsiveness to HDAC4 and -5, we performed yeast two-hybrid screens to identify HDAC-interacting factors. These screens revealed interactions between HDAC4 and members of the 14-3-3 family of proteins, which function as signal-dependent intracellular chaperones. HDAC4 binds constitutively to 14-3-3 in yeast and mammalian cells, whereas HDAC5 binding to 14-3-3 is largely dependent on CaMK signaling. CaMK phosphorylates serines -259 and -498 in HDAC5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to HDAC5 is required for CaMK-dependent disruption of MEF2-HDAC complexes and nuclear export of HDAC5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.

Class II histone deacetylases: versatile regulators

“…Overexpression of constitutively active CaMKs or signal-dependent activation of CaMKs induces the relocalization of class IIa HDACs to the cytoplasm and suppresses their repressive activity [22,47]. By contrast, mutation of the phosphorylation sites of class IIa HDACs abolishes their cytoplasmic export and enhances their repressive effects during muscle differentiation and T-cell apoptosis [40,43].…”

“…Expression of an HDAC -VP16 fusion protein, in which the VP16 activation domain replaces the catalytic domain of HDAC4 or -5, enhances myogenic conversion [47]. Activation of the CaMK signaling pathway also overcomes the HDAC-mediated repression of muscle-specific gene expression and induces the myogenic conversion program [22,64]. Further evidence for the role of class IIa HDACs in cardiac and skeletal myogenesis comes from the phenotype of HDAC9-deficient animals.…”

Class IIa histone deacetylases: regulating the regulators

“…It was proposed that mitochondrial targeting and processing of HDAC7 may act as an irreversible intracellular reservoir to sequester HDAC7, which would otherwise be available for nucleocytoplasmic trafficking (Bakin and Jung, 2004). Class IIa HDACs can localize into specific subnuclear structures and HDAC5 has been found to form dot-like nuclear structures, termed matrix-associated deacetylase bodies Wang et al, 1999;Downes et al, 2000;McKinsey et al, 2000b). In response to DNA damage, HDAC4 is recruited to nuclear repair foci, together with the DNA damage response protein 53BP1 .…”

“…Association with 14-3-3 and other cellular proteins Association with 14-3-3 proteins soon appeared as a critical factor in the regulation of class IIa HDAC subcellular localization (Grozinger and Schreiber, 2000; Class IIa histone deacetylases M Martin et al McKinsey et al, 2000b;Wang et al, 2000;Kao et al, 2001). As observed for most 14-3-3 binding partners (Muslin et al, 1996), this association is dependent on the phosphorylation of interacting motifs within class IIa HDACs.…”

CRM1 mediates nuclear export of HDAC7 independently of HDAC7 phosphorylation and association with 14‐3‐3s

“…An important feature of the class IIa HDACs is their ability to shuttle between the nucleus and the cytoplasm. Precise regulation of the subcellular distribution of class IIa HDACs plays a pivotal role in cellular processes and organ development, including muscle differentiation [14][15][16], heart development [17], thymus development [18], and skeletogenesis [19].…”