The E3 ubiquitin ligase specificity subunit ASB2beta is a novel regulator of muscle differentiation that targets filamin B to proteasomal degradation.
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, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation. Thus, ASB2beta regulates FLNb functions by controlling its degradation. Knockdown of endogenous ASB2beta 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 ASB2beta knockdown cells restores myogenic differentiation. Altogether, our results suggest that ASB2beta is involved in muscle differentiation through the targeting of FLNb to destruction by the proteasome.
Bello
N F
NF
Institut de Pharmacologie et de Biologie Structurale, CNRS, Toulouse, France.
Lamsoul
I
I
Heuzé
M L
ML
Métais
A
A
Moreaux
G
G
Calderwood
D A
DA
Duprez
D
D
Moog-Lutz
C
C
Lutz
P G
PG
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002645:Chickens; D003285:Contractile Proteins / Q000172:deficiency / Q000378:metabolism*; D064448:Filamins; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000172:deficiency / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C542087:Asb2 protein, mouse; D002352:Carrier Proteins; D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D008840:Microfilament Proteins; D012333:RNA, Messenger; D050826:Suppressor of Cytokine Signaling Proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex