Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo.
Inhibitor of apoptosis proteins (IAPs) c-IAP1 and c-IAP2 were identified as part of the tumor necrosis factor receptor 2 (TNFR2) signaling complex and have been implicated as intermediaries in tumor necrosis factor alpha signaling. Like all RING domain-containing IAPs, c-IAP1 and c-IAP2 have ubiquitin protein ligase (E3) activity. To explore the function of c-IAP1 in a physiologic setting, c-IAP1-deficient mice were generated by homologous gene recombination. These animals are viable and have no obvious sensitization to proapoptotic stimuli. Cells from c-IAP1(-/-) mice do, however, express markedly elevated levels of c-IAP2 protein in the absence of increased c-IAP2 mRNA. In contrast to reports implicating c-IAPs in the activation of NF-kappaB, resting and cytokine-induced NF-kappaB activation was not impaired in c-IAP1-deficient cells. Transient transfection studies with wild-type and E3-defective c-IAP1 revealed that c-IAP2 is a direct target for c-IAP1-mediated ubiquitination and subsequent degradation, which are potentiated by the adaptor function of TRAF2. Thus, the c-IAPs represent a pair of TNFR-associated ubiquitin protein ligases in which one regulates the expression of the other by a posttranscriptional and E3-dependent mechanism.
Conze
Dietrich B
DB
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 37, Room 3002, Bethesda, MD 20892, USA.
Albert
Lori
L
Ferrick
David A
DA
Goeddel
David V
DV
Yeh
Wen-Chen
WC
Mak
Tak
T
Ashwell
Jonathan D
JD
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015536:Down-Regulation; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; D047992:TNF Receptor-Associated Factor 2; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494834:Birc2 protein, mouse; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases