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The role of TRAF2 and TRAF5 in TNFα-induced NF-κB activation has become complicated due to accumulation of conflicting data. Here, we report that 7-day old TRAF2 knockout (KO) and TRAF2/TRAF5 double KO (TRAF2/5 DKO) mice exhibit enhanced canonical IKK and caspase-8 activation in spleen and liver, and that subsequent KO of TNFα suppresses the basal activity of caspase-8, but not of IKK. In primary TRAF2 KO and TRAF2/5 DKO cells, while TNFα-induced immediate IKK activation is impaired, delayed IKK activation occurs normally; as such, due to elevated basal and TNFα-induced delayed IKK activation, TNFα stimulation leads to significantly increased induction of a subset of NF-κB-dependent genes in these cells. In line with this, both TRAF2 KO and TRAF2/5 DKO mice succumb to a sublethal dose of TNFα, due to increased expression of NF-κB target genes, diarrhea and bradypnea. Notably, depletion of cIAP1/2 also results in elevated basal IKK activation independent of autocrine TNFα production and impairs TNFα-induced immediate IKK activation. These data reveal that TRAF2 and cIAP1/2, but not TRAF5, cooperatively regulate basal and TNFα-induced immediate IKK activation.

TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classical IKK complex in hematopoietic cells