A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program.
Prolonged deficits in neural input activate pathological muscle remodeling, leading to atrophy. In denervated muscle, activation of the atrophy program requires HDAC4, a potent repressor of the master muscle transcription factor MEF2. However, the signaling mechanism that connects HDAC4, a protein deacetylase, to the atrophy machinery remains unknown. Here, we identify the AP1 transcription factor as a critical target of HDAC4 in neurogenic muscle atrophy. In denervated muscle, HDAC4 activates AP1-dependent transcription, whereas AP1 inactivation recapitulates HDAC4 deficiency and blunts the muscle atrophy program. We show that HDAC4 activates AP1 independently of its canonical transcriptional repressor activity. Surprisingly, HDAC4 stimulates AP1 activity by activating the MAP kinase cascade. We present evidence that HDAC4 binds and promotes the deacetylation and activation of a key MAP3 kinase, MEKK2. Our findings establish an HDAC4-MAPK-AP1 signaling axis essential for neurogenic muscle atrophy and uncover a direct crosstalk between acetylation- and phosphorylation-dependent signaling cascades.
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Moon-Chang
MC
Choi
Todd J
TJ
Cohen
Tomasa
T
Barrientos
Bin
B
Wang
Ming
M
Li
Bryan J
BJ
Simmons
Jeong Soo
JS
Yang
Gregory A
GA
Cox
Yingming
Y
Zhao
Tso-Pang
TP
Yao
D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048730:MAP Kinase Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D018808:Transcription Factor AP-1; D048730:MAP Kinase Kinase Kinase 2; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases