The E3 ubiquitin ligase specificity subunit ASB2β 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, ASB2 beta, is important for muscle differentiation. ASB2 beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2 beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation. Thus, ASB2 beta regulates FLNb functions by controlling its degradation. Knockdown of endogenous ASB2 beta 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 beta knockdown cells restores myogenic differentiation. Altogether, our results suggest that ASB2 beta is involved in muscle differentiation through the targeting of FLNb to destruction by the proteasome. Cell Death and Differentiation (2009) 16, 921-932; doi: 10.1038/cdd.2009.27; published online 20 March 2009