Résumé :
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The covalent linkage of a polyubiquitin chain to a protein and its subsequent targeting to the 26S proteasome is one of the major mechanisms for controlled proteolysis. The specificity of this degradation pathway is due to E3 ubiquitin ligases involved in the recruitment of specific substrate(s). Ubiquitin-mediated protein degradation is crucial for muscle development and for maintenance of muscle homeostasis. The ubiquitin-proteasome pathway also regulates the rapid proteolysis associated with muscle wasting which is induced by metabolic or catabolic diseases. However, few E3 ubiquitin ligases involved in these processes and their specific substrates have been described so far. The ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2 (ASB2) gene that we originally identified as induced during differentiation of myeloid leukaemia cells encodes the specificity subunit of a multimeric E3 ubiquitin ligase complex. This suggests that ASB2 regulates the stability of specific proteins via their polyubiquitination and proteosomal degradation. We provide the first evidence that a novel ASB2 isoform, ASB2?, is expressed in muscle cells during embryogenesis and in adult tissues. ASB2? expression is also induced during in vitro muscle differentiation and appeared with the differentiation commitment of C2C12 myoblasts. Its inhibition by shRNAs during induced-differentiation of C2C12 cells delayed myotube formation and expression of muscle contractile proteins. Moreover, ASB2? is upregulated during induced-atrophy of C2C12 myotubes suggesting that it might be also involved in this catabolic state. We also showed that ASB2? can assemble with the Elongin BC complex and a Cullin5/Rbx2 module to reconstitute an active E3 ubiquitin ligase complex. Altogether, our results suggest that ASB2? is involved in muscle differentiation likely through the targeting of crucial muscle proteins to destruction by the proteasome.
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