Alpha-actinin 4 potentiates myocyte enhancer factor-2 transcription activity by antagonizing histone deacetylase 7.
Histone deacetylase 7 (HDAC7) is a member of class IIa HDACs that regulate myocyte enhancer factor-2 (MEF2)-mediated transcription and participate in multiple cellular processes such as T cell apoptosis. We have identified alpha-actinin 1 and 4 as class IIa HDAC-interacting proteins. The interaction domains are mapped to C terminus of alpha-actinin 4 and amino acids 72-172 of HDAC7. A point mutation in HDAC7 that disrupts its association with MEF2A also disrupts its association with alpha-actinin 4, indicating that MEF2A and alpha-actinin 4 binding sites largely overlap. We have also isolated a novel splice variant of alpha-actinin 4 that is predominantly localized in the nucleus, a pattern distinct from the full-length alpha-actinin 4, which is primarily distributed in the cytoplasm and plasma membrane. Using small interfering RNA, chromatin immunoprecipitation, and transient transfection assays, we show that alpha-actinin 4 potentiates expression of TAF55, a putative MEF2 target gene. Loss of MEF2A interaction correlates with loss of the ability of alpha-actinin 4 to potentiate TAF55 promoter activity. Ectopic expression of alpha-actinin 4, but not the mutant defective in MEF2A association, leads to disruption of HDAC7.MEF2A association and enhancement of MEF2-mediated transcription. Taken together, we have identified a novel mechanism by which HDAC7 activity is negatively regulated and uncovered a previously unknown function of alpha-actinin 4.
Chakraborty
Sharmistha
S
Department of Biochemistry, School of Medicine, Case Western Reserve University, and the Research Institute of University Hospitals of Cleveland, OH 44106, USA.
Reineke
Erin L
EL
Lam
Minh
M
Li
Xiaofang
X
Liu
Yu
Y
Gao
Chengzhuo
C
Khurana
Simran
S
Kao
Hung-Ying
HY
D000185:Actinin / Q000378:metabolism*; D000595:Amino Acid Sequence; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D008840:Microfilament Proteins / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
C111453:ACTN4 protein, human; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D008840:Microfilament Proteins; D018006:Myogenic Regulatory Factors; D000185:Actinin; C543273:HDAC7 protein, human; D006655:Histone Deacetylases