Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis.
Histone deacetylases (HDACs) are important regulators of gene expression as part of transcriptional corepressor complexes. Here, we demonstrate that caspases can repress the activity of the myocyte enhancer factor (MEF)2C transcription factor by regulating HDAC4 processing. Cleavage of HDAC4 occurs at Asp 289 and disjoins the carboxy-terminal fragment, localized into the cytoplasm, from the amino-terminal fragment, which accumulates into the nucleus. In the nucleus, the caspase-generated fragment of HDAC4 is able to trigger cytochrome c release from mitochondria and cell death in a caspase-9-dependent manner. The caspase-cleaved amino-terminal fragment of HDAC4 acts as a strong repressor of the transcription factor MEF2C, independently from the HDAC domain. Removal of amino acids 166-289 from the caspase-cleaved fragment of HDAC4 abrogates its ability to repress MEF2 transcription and to induce cell death. Caspase-2 and caspase-3 cleave HDAC4 in vitro and caspase-3 is critical for HDAC4 cleavage in vivo during UV-induced apoptosis. After UV irradiation, GFP-HDAC4 translocates into the nucleus coincidentally/immediately before the retraction response, but clearly before nuclear fragmentation. Together, our data indicate that caspases could specifically modulate gene repression and apoptosis through the proteolyic processing of HDAC4.
Paroni
Gabriela
G
Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia-Università di Udine, 33100 Udine, Italy.
Mizzau
Michela
M
Henderson
Clare
C
Del Sal
Giannino
G
Schneider
Claudio
C
Brancolini
Claudio
C
D017209:Apoptosis; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D017930:Genes, Reporter / Q000235:genetics; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection
D061945:Caspase Inhibitors; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; D011994:Recombinant Proteins; D012097:Repressor Proteins; D020169:Caspases; C400300:HDAC4 protein, human; D006655:Histone Deacetylases