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 d...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Molecular cell 2012-07, Vol.47 (1), p.122-132
Hauptverfasser: Choi, Moon-Chang, Cohen, Todd J., Barrientos, Tomasa, Wang, Bin, Li, Ming, Simmons, Bryan J., Yang, Jeong Soo, Cox, Gregory A., Zhao, Yingming, Yao, Tso-Pang
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. ► HDAC4 targets the AP1 but not MEF2 transcription program in neurogenic muscle atrophy ► HDAC4 stimulates AP1 activity by activating MAP kinase signaling ► HDAC4 activates the MAPK cascade by promoting the deacetylation a MAP3K, MEKK2 ► The HDAC4-MAPK-AP1 signaling cascade is essential for neurogenic muscle atrophy
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2012.04.025