New insights into the role of the ubiquitin-proteasome pathway in the regulation of apoptosis.
The ubiquitin-proteasome pathway (UPP) is the major system responsible for degradation of intracellular proteins in eukaryotes. By controlling the levels of key proteins, it regulates almost all of the cellular activities, including cell cycle progression, DNA replication and repair, transcription, protein quality control, immune response, and apoptosis. UPP is composed of the ubiquitination system that marks proteins for degradation and the proteasome which degrades the ubiquitinated proteins. The 26S proteasome is a 2400 kDa complex consisting of more than 40 subunits. Following ubiquitination catalyzed by the ubiquitin activating enzyme (El), a ubiquitin-carrier protein (E2), and one of the cell's many ubiquitin-protein ligases (E3s), the protein substrates are targeted to the proteasome for degradation into small peptides. E3s regulate the degradation of protein substrates indirectly by determining both the specificity and timing of substrate ubiquitination, whereas the deubiquitinating enzymes can inhibit this process by releasing ubiquitin from substrates. In this review, we attempt to highlight the recent progress in research on UPP and its role in the regulation of apoptosis by focusing on several of its important components, including the ubiqutin ligase Nrdp 1, which regulates ErbB/EGFR family of receptor tyrosine kinases, the ubiquitin-carrier protein BRUCE/Apollon (an Inhibitor of Apoptosis Protein), and the novel proteasome subunit hRpnl3 (a binding site for the deubiquitinating enzyme, UCH37).
Liu
Cui-Hua
CH
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing, China.
Goldberg
Alfred L
AL
Qiu
Xiao-Bo
XB
D000818:Animals; D017209:Apoptosis; D002268:Carboxypeptidases / Q000502:physiology; D002384:Catalysis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D021122:Protein Subunits; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
C401541:BIRC6 protein, human; D051034:Inhibitor of Apoptosis Proteins; D021122:Protein Subunits; D025801:Ubiquitin; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases; D002268:Carboxypeptidases; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex