Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli.
To determine why proteasome inhibitors prevent thymocyte death, we examined whether proteasomes degrade anti-apoptotic molecules in cells induced to undergo apoptosis. The c-IAP1 and XIAP inhibitors of apoptosis were selectively lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome-dependent manner before death. IAPs catalyzed their own ubiquitination in vitro, an activity requiring the RING domain. Overexpressed wild-type c-IAP1, but not a RING domain mutant, was spontaneously ubiquitinated and degraded, and stably expressed XIAP lacking the RING domain was relatively resistant to apoptosis-induced degradation and, correspondingly, more effective at preventing apoptosis than wild-type XIAP. Autoubiquitination and degradation of IAPs may be a key event in the apoptotic program.
Yang
Y
Y
Laboratory of Immune Cell Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Fang
S
S
Jensen
J P
JP
Weissman
A M
AM
Ashwell
J D
JD
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006825:Hybridomas; D051034:Inhibitor of Apoptosis Proteins; D008025:Ligases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
D051034:Inhibitor of Apoptosis Proteins; D009097:Multienzyme Complexes; D011506:Proteins; D011993:Recombinant Fusion Proteins; D014452:Ubiquitins; D051636:X-Linked Inhibitor of Apoptosis Protein; D005047:Etoposide; D003907:Dexamethasone; C494834:Birc2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases