title: Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation.
abstract: The cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2) proteins have been implicated in the activation of NF-kappaB by TNFalpha; however, genetic deletion of either cIAP1 or 2 did not support a physiologically relevant role, perhaps because of functional redundancy. To address this, we used combined genetic and siRNA knockdown approaches and report that cIAP1 and 2 are indeed critical, yet redundant, regulators of NF-kappaB activation upon TNFalpha treatment. Whereas NF-kappaB was properly activated by TNFalpha in cultured and primary cells deficient in either cIAP1 or 2, removal of both cIAPs severely blunted its activation. After treatment with TNFalpha, cIAP1 and 2 were rapidly recruited to the TNF receptor 1, along with the adapter protein TNF receptor associated factor 2. Importantly, either cIAP1 or 2 was required for proper TNF receptor 1 signalosome function. In their combined absence, polyubiquitination of receptor interacting protein 1, an upstream event necessary for NF-kappaB signaling, was attenuated. As a result, phosphorylation of the inhibitor of kappaB kinase beta was diminished, and signal transduction was severely blunted. Consequently, cells missing both cIAP1 and 2 were sensitized to TNFalpha-mediated apoptosis. Collectively, these data demonstrate that either cIAP1 or 2 is required for proper Rip1 polyubiquitination and NF-kappaB activation upon TNFalpha treatment.
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada K1H 8L1.
authors.forename: D J
authors.initials: DJ
authors.lastname: Mahoney
authors.forename: H H
authors.initials: HH
authors.lastname: Cheung
authors.forename: R Lejmi
authors.initials: RL
authors.lastname: Mrad
authors.forename: S
authors.initials: S
authors.lastname: Plenchette
authors.forename: C
authors.initials: C
authors.lastname: Simard
authors.forename: E
authors.initials: E
authors.lastname: Enwere
authors.forename: V
authors.initials: V
authors.lastname: Arora
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.forename: E C
authors.initials: EC
authors.lastname: Lacasse
authors.forename: J
authors.initials: J
authors.lastname: Waring
authors.forename: R G
authors.initials: RG
authors.lastname: Korneluk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D020690:GTPase-Activating Proteins / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D054875:Ubiquitination
chemical_list: D020690:GTPase-Activating Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C490620:Ralbp1 protein, mouse; D053199:TNF Receptor-Associated Death Domain Protein; C481226:Tradd protein, mouse; D014409:Tumor Necrosis Factor-alpha