Dephosphorylation of HDAC4 by PP2A-Bδ unravels a new role for the HDAC4/MEF2 axis in myoblast fusion

Abstract

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-B55δ holoenzyme is necessary for skeletal myogenesis. The primary role of PP2A-B55δ 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-B55δ 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-B55δ severely impairs fusion of myocytes and formation of multinucleated muscle fibers, without affecting myoblast differentiation. Taken together, our results establish PP2A-B55δ 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.

HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle

“…Of interest, HDAC4 protein is more abundant in the slow SL muscle, although the basis of this discrepancy is not known yet [27]. The main role of HDAC4 in myogenesis has been extensively studied and is through direct repression of MEF2, the master regulator of slow fiber program [4, [28][29][30][31]. In addition, HDAC4 expression is upregulated upon muscle injury and it is essential for an appropriate muscle regeneration [32][33][34].…”

Refining the Class IIa HDAC/MEF2 Paradigm in Muscle Biology: More than Meets the Eye

“…In muscle cells, we succeeded in identifying HDAC4 as the specific substrate of PP2A holoenzymes containing the Bδ regulatory subunit. Interestingly, other class IIa HDACs were not regulated by PP2A-Bδ [4].…”

“…The original goal of our study was to investigate the role of protein phosphatases during myogenesis [4]. Because protein kinases have long been known to be crucial in this process, the involvement of their counterpart, protein phosphatases would also be expected.…”

“…The class IIa Histone DeACetylases (HDACs)/MEF2 (Myocyte Enhancer Factor-2) axis has long being considered as the master regulator of the differentiation process during skeletal myogenesis [3]. However, our recent work [4] demonstrates that this pathway is also crucial for fusion of myocytes into myofibers, both in vitro and in vivo. Our findings thus further confirm and expend the idea that the class IIa HDACs/MEF2 axis is a cornerstone of the myogenic process in vertebrates.…”

The cytoskeleton adaptor protein Sorbs1 controls the development of lymphatic and venous vessels in zebrafish

“…Indeed, we demonstrate that Sorbs1 acts upstream of RhoGTPases to control EC actomyosin cytoskeleton and migratory behavior. Prior to this work, only few studies had alluded to potential connections between SoHo proteins and RhoGTPases signaling50,51,77,78 . Although extension of filopodia and migration of leading ECs during BMP-induced CVP morphogenesis was shown to be dependent on the Cdc42 RhoGTPase71 , we found that Cdc42 activity was not affected in the absence of Sorbs1 in ECs.…”