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Title: TRAF2 exerts opposing effects on basal and TNFα-induced activation of the classic IKK complex in hematopoietic cells in mice.

Authors: Zhang, Laiqun; Blackwell, Ken; Workman, Lauren M; Gibson-Corley, Katherine N; Olivier, Alicia K; Bishop, Gail A; Habelhah, Hasem

Published In J Cell Sci, (2016 Apr 01)

Abstract: The role of TRAF2 and TRAF5 in TNFα-induced NF-κB activation has become complicated owing to the 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 IκB kinase (IKK) and caspase-8 activation in spleen and liver, and that subsequent knockout of TNFα suppresses the basal activity of caspase-8, but not of IKK. In primary TRAF2 KO and TRAF2/5-DKO cells, TNFα-induced immediate IKK activation is impaired, whereas delayed IKK activation occurs normally; as such, owing 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 owing to increased expression of NF-κB target genes, diarrhea and bradypnea. Notably, depletion of IAP1 and IAP2 (also known as BIRC2 and BIRC3, respectively) also results in elevated basal IKK activation that is independent of autocrine TNFα production and that impairs TNFα-induced immediate IKK activation. These data reveal that TRAF2, IAP1 and IAP2, but not TRAF5, cooperatively regulate basal and TNFα-induced immediate IKK activation.

PubMed ID: 26872784 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis/genetics; Baculoviral IAP Repeat-Containing 3 Protein; Caspase 8/metabolism*; Cells, Cultured; Chemokine CCL5/metabolism; Enzyme Activation/genetics; I-kappa B Kinase/genetics; I-kappa B Kinase/metabolism*; Inhibitor of Apoptosis Proteins/deficiency; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B/metabolism*; Nitric Oxide Synthase Type II/metabolism; TNF Receptor-Associated Factor 2/genetics; TNF Receptor-Associated Factor 2/metabolism*; TNF Receptor-Associated Factor 5/genetics; TNF Receptor-Associated Factor 5/metabolism*; Tumor Necrosis Factor-alpha/genetics; Tumor Necrosis Factor-alpha/metabolism*; Ubiquitin-Protein Ligases/deficiency

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