title: Caspase activation inhibits proteasome function during apoptosis.
abstract: The ubiquitin/proteasome system regulates protein turnover by degrading polyubiquitinated proteins. To date, all studies on the relationship of apoptosis and the proteasome have emphasized the key role of the proteasome in the regulation of apoptosis, by virtue of its ability to degrade regulatory molecules involved in apoptosis. We now demonstrate how induction of apoptosis may regulate the activity of the proteasome. During apoptosis, caspase activation results in the cleavage of three specific subunits of the 19S regulatory complex of the proteasome: S6' (Rpt5) and S5a (Rpn10), whose role is to recognize polyubiquitinated substrates of the proteasome, and S1 (Rpn2), which with S5a and S2 (Rpn1) holds together the lid and base of the 19S regulatory complex. This caspase-mediated cleavage inhibits the proteasomal degradation of ubiquitin-dependent and -independent cellular substrates, including proapoptotic molecules such as Smac, so facilitating the execution of the apoptotic program by providing a feed-forward amplification loop.
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester, LE1 9HN, United Kingdom.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Sun
authors.forename: Michael
authors.initials: M
authors.lastname: Butterworth
authors.forename: Marion
authors.initials: M
authors.lastname: MacFarlane
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dubiel
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Cohen
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D005047:Etoposide / Q000378:metabolism; D006023:Glycoproteins; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D015938:Complement Membrane Attack Complex; C412403:DIABLO protein, human; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D019384:Nucleic Acid Synthesis Inhibitors; D021122:Protein Subunits; C047610:SC5b-9 protein complex; D025801:Ubiquitin; D005047:Etoposide; D003165:Complement System Proteins; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex