title: USP19 deubiquitinating enzyme inhibits muscle cell differentiation by suppressing unfolded-protein response signaling.
abstract: The USP19 deubiquitinating enzyme modulates the expression of myogenin and myofibrillar proteins in L6 muscle cells. This raised the possibility that USP19 might regulate muscle cell differentiation. We therefore tested the effects of adenoviral-mediated overexpression or small interfering RNA (siRNA)-mediated silencing of either the cytoplasmic or endoplasmic reticulum (ER)-localized isoforms of USP19. Only the ER-localized isoform of USP19 (USP19-ER) modulated myoblast fusion as well as the expression of myogenin and myofibrillar proteins, and these effects were also dependent on USP19 catalytic activity. USP19-ER inhibited muscle cell differentiation and the induction of CHOP, a transcription factor in the unfolded-protein response (UPR) that is activated during differentiation. Inducing the UPR by creating mild ER stress with thapsigargin was able to reverse the defect in myoblast fusion caused by the overexpression of USP19-ER, suggesting strongly that USP19 exerts its effects on fusion through its effects on UPR signaling. USP19 also functions similarly in vivo, as USP19(-/-) mice display improved muscle regeneration concomitant with enhanced expression of CHOP. Collectively these results implicate a deubiquitinating enzyme as a regulator of the UPR. They also suggest that inhibition of USP19 may be a therapeutic approach for the enhancement of muscle growth following injury.
authors.affiliation: Polypeptide Laboratory, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada Department of Medicine, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada Department of Biochemistry, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wiles
authors.affiliation: Polypeptide Laboratory, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada Department of Medicine, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada.
authors.forename: Miao
authors.initials: M
authors.lastname: Miao
authors.affiliation: Polypeptide Laboratory, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada Department of Medicine, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada Department of Biochemistry, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Coyne
authors.affiliation: Polypeptide Laboratory, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada Department of Medicine, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada.
authors.forename: Louise
authors.initials: L
authors.lastname: Larose
authors.affiliation: Department of Medicine, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Cybulsky
authors.affiliation: Polypeptide Laboratory, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada Department of Medicine, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada Department of Biochemistry, McGill University and McGill University Health Centre Research Institute, Montreal, QC H3A OC7, Canada simon.wing@mcgill.ca.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Wing
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology*; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: C497250:Ddit3 protein, mouse; C497251:Ddit3 protein, rat; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D010450:Endopeptidases; C000600175:USP19 protein, mouse