Dephosphorylation and Caspase Processing Generate Distinct Nuclear Pools of Histone Deacetylase 4▿ †

From the nucleus, histone deacetylase 4 (HDAC4) regulates a variety of cellular processes, including growth, differentiation, and survival, by orchestrating transcriptional changes. Extracellular signals control its repressive influence mostly through regulating its nuclear-cytoplasmic shuttling. In particular, specific posttranslational modifications such as phosphorylation and caspase-mediated proteolytic processing operate on HDAC4 to promote its nuclear accumulation or export. To understand the signaling properties of this deacetylase, we investigated its cell death-promoting activity and the transcriptional repression potential of different mutants that accumulate in the nucleus. Here we show that, compared to that of other nuclear forms of HDAC4, a caspase-generated nuclear fragment exhibits a stronger cell death-promoting activity coupled with increased repressive effect on Runx2- or SRF-dependent transcription. However, this mutant displays reduced repressive action on MEF2C-driven transcription. Photobleaching experiments and quantitative analysis of the raw data, based on a two-binding-state compartmental model, demonstrate the existence of two nuclear pools of HDAC4 with different chromatin-binding properties. The caspase-generated fragment is weakly bound to chromatin, whereas an HDAC4 mutant defective in 14-3-3 binding or the wild-type HDAC5 protein forms a more stable complex. The tightly bound species show an impaired ability to induce cell death and repress Runx2- or SRF-dependent transcription less efficiently. We propose that, through specific posttranslation modifications, extracellular signals control two distinct nuclear pools of HDAC4 to differentially dictate cell death and differentiation. These two nuclear pools of HDAC4 are characterized by different repression potentials and divergent dynamics of chromatin interaction

Histone deacetylase 4 promotes cholestatic liver injury in the absence of prohibitin-1

Prohibitin 1 (PHB1) is an evolutionary conserved pleiotropic protein that participates in diverse processes depending on its subcellular localization and interactome. Recent data have indicated a diverse role for PHB1 in the pathogenesis of obesity, cancer and inflammatory bowel disease, among others. Data presented here suggest that PHB1 is also linked to cholestatic liver disease. PHB1 expression is markedly reduced in patients with primary billiary cirrhosis and biliary atresia and Alagille syndrome, two major pediatric cholestatic conditions. In the experimental model of bile duct ligation, silencing of PHB1 induced liver fibrosis, reduced animal survival and induced bile duct proliferation. Importantly, the modulatory effect of PHB1 is not dependent on its known mitochondrial function. Importantly, d PHB1 interacts with Histone Deacetylase 4 (HDAC4) in the presence of bile acids. Hence, PHB1 depletion leads to increased nuclear HDAC4 content and its associated epigenetic changes. Remarkably, HDAC4 silencing and the administration of the HDAC inhibitor parthenolide during obstructive cholestasis in vivo promote genomic reprogramming leading to the regression of the fibrotic phenotype in the liver-specific Phb1 KO mice. CONCLUSION: Our data identify PHB1 as an important mediator of cholestatic liver injury regulating the activity of HDAC4, which controls specific epigenetic marks. These results identify potential novel strategies to treat liver injury and fibrosis, particularly as a consequence of chronic cholestasis

Ubiquitin-dependent degradation of HDAC4, a new regulator of random cell motility

Histone deacetylase 4 (HDAC4) controls several cellular responses and is subjected to multiple levels of regulation. Here it is shown that HDAC4 is under the regulation of the proteasome, in a growth factor- and GSK3β-dependent manner. Degradation of HDAC4 could contribute to the attenuation of random cell motility observed in cells in the G0 phase of the cell cycle