title: TRAF2 suppresses basal IKK activity in resting cells and TNFalpha can activate IKK in TRAF2 and TRAF5 double knockout cells.
abstract: Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) and TRAF5 are adapter proteins involved in TNFalpha-induced activation of the c-Jun N-terminal kinase and nuclear factor kappaB (NF-kappaB) pathways. Currently, TNFalpha-induced NF-kappaB activation is believed to be impaired in TRAF2 and TRAF5 double knockout (T2/5 DKO) cells. Here, we report instead that T2/5 DKO cells exhibit high basal IkappaB kinase (IKK) activity and elevated expression of NF-kappaB-dependent genes in unstimulated conditions. Although TNFalpha-induced receptor-interacting protein 1 ubiquitination is indeed impaired in T2/5 DKO cells, TNFalpha stimulation further increases IKK activity in these cells, resulting in significantly elevated expression of NF-kappaB target genes to a level higher than that in wild-type cells. Inhibition of NIK in T2/5 DKO cells attenuates basal IKK activity and restores robust TNFalpha-induced IKK activation to a level comparable with that seen in wild-type cells. This suggests that TNFalpha can activate IKK in the absence of TRAF2 and TRAF5 expression and receptor-interacting protein 1 ubiquitination. In addition, both the basal and TNFalpha-induced expression of anti-apoptotic proteins are normal in T2/5 DKO cells, yet these DKO cells remain sensitive to TNFalpha-induced cell death, due to the impaired recruitment of anti-apoptotic proteins to the TNFR1 complex in the absence of TRAF2. Thus, our data demonstrate that TRAF2 negatively regulates basal IKK activity in resting cells and inhibits TNFalpha-induced cell death by recruiting anti-apoptotic proteins to the TNFR1 complex rather than by activating the NF-kappaB pathway.
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, 1173ML, Iowa City, IA 52242-1087, USA.
authors.forename: Laiqun
authors.initials: L
authors.lastname: Zhang
authors.forename: Ken
authors.initials: K
authors.lastname: Blackwell
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Thomas
authors.forename: Shujie
authors.initials: S
authors.lastname: Sun
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Hasem
authors.initials: H
authors.lastname: Habelhah
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D055786:Gene Knockout Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D048015:TNF Receptor-Associated Factor 5; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases