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Regulation of Protein Catabolism by Muscle-Specific and Cytokine-Inducible Ubiquitin Ligase E3-II during Cancer Cachexia

¹ Department of Metabolic Disorders, Oncology & Discovery Research, Amgen Inc., Thousand Oaks, California; and ² Laboratory of Protein Catabolism, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

The progressive depletion of skeletal muscle is a hallmark of many types of advanced cancer and frequently is associated with debility, morbidity, and mortality. Muscle wasting is primarily mediated by the activation of the ubiquitin-proteasome system, which is responsible for degrading the bulk of intracellular proteins. E3 ubiquitin ligases control polyubiquitination, a rate-limiting step in the ubiquitin-proteasome system, but their direct involvement in muscle protein catabolism in cancer remains obscure. Here, we report the full-length cloning of E3-II, a novel "N-end rule" ubiquitin ligase, and its functional involvement in cancer cachexia. E3-II is highly enriched in skeletal muscle, and its expression is regulated by proinflammatory cytokines. In two different animal models of cancer cachexia, E3-II was significantly induced at the onset and during the progression of muscle wasting. The E3-II activation in skeletal muscle was accompanied by a sharp increase in protein ubiquitination, which could be blocked by arginine methylester, an E3-selective inhibitor. Treatment of myotubes with tumor necrosis factor or interleukin 6 elicited marked increases in E3-II but not E3-I expression and ubiquitin conjugation activity in parallel. E3-II transfection markedly accelerated ubiquitin conjugation to endogenous cellular proteins in muscle cultures. These findings show that E3-II plays an important role in muscle protein catabolism during cancer cachexia and suggest that E3-II is a potential therapeutic target for muscle wasting.

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