cIAP1, cIAP2, and XIAP act cooperatively via nonredundant pathways to regulate genotoxic stress-induced nuclear factor-kappaB activation.
Various genotoxic agents cause monoubiquitination of NEMO/IKKgamma-the regulatory subunit of IkappaB kinase (IKK) complex-in the nucleus. Ubiquitinated NEMO exits from the nucleus and forms a complex with the IKK catalytic subunits IKKalpha and IKKbeta, resulting in IKK activation and, ultimately, nuclear factor-kappaB (NF-kappaB) activation. Thus, NEMO ubiquitination is a prerequisite for IKK-dependent activation of NF-kappaB. However, the IKK activation mechanism is unknown and the NEMO-ubiquitinating E3 enzyme has not been identified. We found that inhibitors of apoptosis protein (IAP) regulate genotoxic stress-induced NF-kappaB activation at different levels. XIAP mediates activation of the upstream IKK kinase, TAK1, and couples activated TAK1 to the IKK complex. This XIAP-dependent event occurs in response to camptotechin or etoposide/VP16; however, XIAP is dispensable for activation of NF-kappaB by doxorubicin, which engages a MEK-ERK pathway to activate IKK. We also show that cIAP1 mediates NEMO ubiquitination and cIAP2 regulates an event downstream of NEMO ubiquitination. Our study highlights nonredundant cooperative contributions of IAPs to antiapoptotic NF-kappaB activation by genotoxic signals beyond their classic caspase inhibitory functions.
Jin
Hyung-Seung
HS
Department of Biology, College of Life Science and Biotechnology and Protein Network Research Center, Yonsei University, Seoul, Republic of Korea.
Lee
Dong-Hee
DH
Kim
Dong-Hwan
DH
Chung
Ji-Hye
JH
Lee
Seul-Ji
SJ
Lee
Tae H
TH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002166:Camptothecin / Q000494:pharmacology; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
D000970:Antineoplastic Agents; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002166:Camptothecin; D004317:Doxorubicin; D005047:Etoposide; D048049:Extracellular Signal-Regulated MAP Kinases; D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein; D000099151:MAP Kinase Kinase Kinase 7; C491731:IKBKG protein, human; C496866:XIAP protein, human; C494832:BIRC3 protein, human