Original Paper
Cell Death and Differentiation (2009) 16, 921–932; doi:10.1038/cdd.2009.27; published online 20 March 2009
The E3 ubiquitin ligase specificity subunit ASB2
is a novel regulator of muscle differentiation that targets filamin B to proteasomal degradation
Edited by G Cossu
N F Bello1,2,7, I Lamsoul1,2,7, M L Heuzé1,2,8, A Métais1,2, G Moreaux1,2, D A Calderwood3,4, D Duprez5,6, C Moog-Lutz1,2,5 and P G Lutz1,2
- 1Institut de Pharmacologie et de Biologie Structurale, CNRS, 205 route de Narbonne, F-31077 Toulouse, France
- 2Université de Toulouse, UPS, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France
- 3Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
- 4Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT 06520, USA
- 5Université Pierre et Marie Curie, Paris, France
- 6CNRS, UMR 7622, Paris, France
Correspondence: PG Lutz or C Moog-Lutz, Institut de Pharmacologie et de Biologie Structurale, UMR 5089 CNRS, 205 Route de Narbonne, F-31077 Toulouse, France. Tel: +33 561 175 471; Fax: +33 561 175 994. E-mails: Pierre.Lutz@ipbs.fr, Christel.Lutz@ipbs.fr
7These authors contributed equally to this work.
8Current address: INSERM U653, Institut Curie, Paris, France.
Received 26 August 2008; Revised 29 January 2009; Accepted 10 February 2009; Published online 20 March 2009.
Abstract
Ubiquitin-mediated protein degradation is the main mechanism for controlled proteolysis, which is crucial for muscle development and maintenance. The ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2 gene (ASB2) encodes the specificity subunit of an E3 ubiquitin ligase complex involved in differentiation of hematopoietic cells. Here, we provide the first evidence that a novel ASB2 isoform, ASB2
, is important for muscle differentiation. ASB2 is expressed in muscle cells during embryogenesis and in adult tissues. ASB2 is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation. Thus, ASB2 regulates FLNb functions by controlling its degradation. Knockdown of endogenous ASB2 by shRNAs during induced differentiation of C2C12 cells delayed FLNb degradation as well as myoblast fusion and expression of muscle contractile proteins. Finally, knockdown of FLNb in ASB2 knockdown cells restores myogenic differentiation. Altogether, our results suggest that ASB2 is involved in muscle differentiation through the targeting of FLNb to destruction by the proteasome.
Keywords:
ubiquitin–proteasome system, ASB2, muscle differentiation, filamin
Abbreviations:
ASB2, ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2 gene; CRL, Cullin RING ligase; FLN, filamin; HECT, homologous to the E6-associated protein C terminus; MHC, myosin heavy chain; MURF, muscle RING finger; RING, really interesting new gene; SOCS, suppressor of cytokine signaling; UIM, ubiquitin-interacting motif; UPS, ubiquitin–proteasome system
