Article (Scientific journals)
Dephosphorylation of HDAC4 by PP2A-Bdelta unravels a new role for the HDAC4/MEF2 axis in myoblast fusion.
Veloso, Alexandra; Martin, Maud; Bruyr, Jonathan et al.
2019In Cell death & disease, 10 (7), p. 512
Peer reviewed


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Abstract :
[en] Muscle formation is controlled by a number of key myogenic transcriptional regulators that govern stage-specific gene expression programs and act as terminal effectors of intracellular signaling pathways. To date, the role of phosphatases in the signaling cascades instructing muscle development remains poorly understood. Here, we show that a specific PP2A-B55delta holoenzyme is necessary for skeletal myogenesis. The primary role of PP2A-B55delta is to dephosphorylate histone deacetylase 4 (HDAC4) following myocyte differentiation and ensure repression of Myocyte enhancer factor 2D (MEF2D)-dependent gene expression programs during myogenic fusion. As a crucial HDAC4/MEF2D target gene that governs myocyte fusion, we identify ArgBP2, an upstream inhibitor of Abl, which itself is a repressor of CrkII signaling. Consequently, cells lacking PP2A-B55delta show upregulation of ArgBP2 and hyperactivation of CrkII downstream effectors, including Rac1 and FAK, precluding cytoskeletal and membrane rearrangements associated with myoblast fusion. Both in vitro and in zebrafish, loss-of-function of PP2A-B55delta severely impairs fusion of myocytes and formation of multinucleated muscle fibers, without affecting myoblast differentiation. Taken together, our results establish PP2A-B55delta as the first protein phosphatase to be involved in myoblast fusion and suggest that reversible phosphorylation of HDAC4 may coordinate differentiation and fusion events during myogenesis.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Veloso, Alexandra
Martin, Maud
Bruyr, Jonathan
O'Grady, Tina ;  Université de Liège - ULiège > Molecular Biology of Diseases-Gene Expression & Cancer
Deroanne, Christophe ;  Université de Liège - ULiège > Cancer-Connective Tissue Biology
Mottet, Denis ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Twizere, Jean-Claude  ;  Université de Liège - ULiège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Molecular Biology of Diseases-Viral Interactomes Network
Cherrier, Thomas 
Dequiedt, Franck   ;  Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales
 These authors have contributed equally to this work.
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Title :
Dephosphorylation of HDAC4 by PP2A-Bdelta unravels a new role for the HDAC4/MEF2 axis in myoblast fusion.
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Journal title :
Cell death & disease
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Peer reviewed :
Peer reviewed
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since 08 August 2019


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