Ubiquitin-protein ligases in muscle wasting.
Muscle wasting occurs when rates of protein degradation outstrip rates of protein synthesis. Accelerated rates of protein degradation develop in atrophying muscle largely through activation of the ubiquitin-proteasome pathway. The complexity of the ubiquitination process, however, has hampered our understanding of how this pathway is activated in atrophying muscles and which enzymes of the ubiquitin conjugation system are responsible. Recent studies demonstrate that two ubiquitin-protein ligases (E3s), atrogin-1/MAFbx and MuRF1 are critical in the development of muscle atrophy. Other experiments implicate E2(14k) and E3alpha, of the N-end rule pathway, as important players in the process. It seems likely that multiple pathways of ubiquitin conjugation are activated in parallel in atrophying muscle, perhaps to target for degradation specific classes of muscle proteins. The emerging challenge will be to define the protein targets for, as well as to develop inhibitors of, these E3s.
Cao
Pei Rang
PR
Renal Unit, DA517, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Kim
Hannah J
HJ
Lecker
Stewart H
SH
D000818:Animals; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D009124:Muscle Proteins / Q000378:metabolism; D009133:Muscular Atrophy / Q000201:enzymology*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases