EGLN3 prolyl hydroxylase regulates skeletal muscle differentiation and myogenin protein stability.
EGLN3, a member of the EGLN family of prolyl hydroxylases, has been shown to catalyze hydroxylation of the alpha subunit of hypoxia-inducible factor-alpha, which targets hypoxia-inducible factor-alpha for ubiquitination by a ubiquitin ligase complex containing the von Hippel-Lindau (VHL) tumor suppressor. We now report that EGLN3 levels increase during C2C12 skeletal myoblast differentiation. EGLN3 small interference RNAs and EGLN3 antisense oligonucleotides blocked C2C12 differentiation and decreased levels of myogenin, a member of the MyoD family of myogenic regulatory factors, which plays a critical role in myogenic differentiation. We also report that EGLN3 interacts with and stabilizes myogenin protein, whereas VHL associates with and destabilizes myogenin via the ubiquitin-proteasome system. The effect of VHL on myogenin stability and ubiquitination can be reversed, at least in part, by overexpression of EGLN3, suggesting that its binding to myogenin may prevent VHL-mediated degradation. These data demonstrate a novel role for EGLN3 in regulating skeletal muscle differentiation and gene expression. In addition, this report provides evidence for a novel pathway that regulates myogenin expression and skeletal muscle differentiation.
Fu
Jian
J
Cardiovascular Research Institute and Department of Medicine, Univeristy of Rochester Medical Center, Rochester, NY 14642, USA. jian_fu@urmc.rochester.edu
Menzies
Keon
K
Freeman
Robert S
RS
Taubman
Mark B
MB
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology*; D002522:Chlorocebus aethiops; D049308:Dioxygenases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D018008:Myogenin / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018008:Myogenin; D025801:Ubiquitin; D049308:Dioxygenases; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D046988:Proteasome Endopeptidase Complex; C497446:VHL protein, human; C494469:VHL protein, mouse