title: Praja1 E3 ubiquitin ligase promotes skeletal myogenesis through degradation of EZH2 upon p38α activation.
abstract: Polycomb proteins are critical chromatin modifiers that regulate stem cell differentiation via transcriptional repression. In skeletal muscle progenitors Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), contributes to maintain the chromatin of muscle genes in a repressive conformation, whereas its down-regulation allows the progression through the myogenic programme. Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372. Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2. Our results indicate that signal-dependent degradation of EZH2 is a prerequisite for satellite cells differentiation and identify PJA1 as a new player in the epigenetic control of muscle gene expression.
authors.affiliation: Laboratory of Epigenetics and Regenerative Pharmacology, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Consalvi
authors.affiliation: Laboratory of Epigenetics and Signal Transduction, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.|Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Via Scarpa 14, Sapienza University, 00161 Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Brancaccio
authors.affiliation: Sanford-Burnham-Prebys Medical Discovery Institute, Development Aging and Regeneration Program, La Jolla 92037, California, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dall'Agnese
authors.affiliation: Laboratory of Epigenetics and Regenerative Pharmacology, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.|Sanford-Burnham-Prebys Medical Discovery Institute, Development Aging and Regeneration Program, La Jolla 92037, California, USA.
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
authors.affiliation: Laboratory of Epigenetics and Signal Transduction, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Palacios
mesh_terms: D000818:Animals; D002460:Cell Line; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics* / Q000378:metabolism; D024510:Muscle Development / Q000235:genetics*; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D010766:Phosphorylation; D055550:Protein Stability; D059748:Proteolysis; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; C109319:Pja1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D048308:Mitogen-Activated Protein Kinase 14