Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia.
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 E3alpha-II, a novel "N-end rule" ubiquitin ligase, and its functional involvement in cancer cachexia. E3alpha-II is highly enriched in skeletal muscle, and its expression is regulated by proinflammatory cytokines. In two different animal models of cancer cachexia, E3alpha-II was significantly induced at the onset and during the progression of muscle wasting. The E3alpha-II activation in skeletal muscle was accompanied by a sharp increase in protein ubiquitination, which could be blocked by arginine methylester, an E3alpha-selective inhibitor. Treatment of myotubes with tumor necrosis factor alpha or interleukin 6 elicited marked increases in E3alpha-II but not E3alpha-I expression and ubiquitin conjugation activity in parallel. E3alpha-II transfection markedly accelerated ubiquitin conjugation to endogenous cellular proteins in muscle cultures. These findings show that E3alpha-II plays an important role in muscle protein catabolism during cancer cachexia and suggest that E3alpha-II is a potential therapeutic target for muscle wasting.
Kwak
Keith S
KS
Department of Metabolic Disorders, Oncology & Discovery Research, Amgen Inc., Thousand Oaks, California 91320, USA.
Zhou
Xiaolan
X
Solomon
Vered
V
Baracos
Vickie E
VE
Davis
James
J
Bannon
Anthony W
AW
Boyle
William J
WJ
Lacey
David L
DL
Han
H Q
HQ
D000595:Amino Acid Sequence; D002100:Cachexia / Q000201:enzymology / Q000378:metabolism*; D003001:Cloning, Molecular; D018076:DNA, Complementary; D006868:Hydrolysis; D015850:Interleukin-6 / Q000502:physiology; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*
D018076:DNA, Complementary; D015850:Interleukin-6; D009124:Muscle Proteins; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases