Abstract 4696: TRAF2 plays a critical role in maintaining lymphocyte homeostasis by regulating the basal activities of IKK and caspase-8

Abstract TRAF2 and TRAF5 are RING domain proteins, and their RING domain-mediated RIP1 ubiquitination is believed to be essential for NF-κB activation and inhibition of caspase-8-mediated cell death in response to TNFα stimulation. We have previously reported instead that TRAF2/5 double knockout (DKO) cells exhibit high basal IKK activity in unstimulated conditions, and that TNFα stimulation further increases IKK activity in the absence of RIP1 ubiquitination in TRAF2/5 DKO cells. These findings potentially revise the currently accepted model for the role of TRAF2/5 in TNFα signaling. However, most of the conclusions in the field regarding the role of TRAF2/5 in TNFα signaling are based on the studies performed in immortalized MEFs, as TRAF2 KO mice die within 10 days after birth. Notably, elimination of either TNFα or TNFR1 enhances the survival of TRAF2 KO mice. Thus, to examine the role of TRAF2 in NF-κB activation versus cell death in primary cells, we generated TRAF2 KO and TNF/TRAF2 DKO mice. Surprisingly, both IKK and caspase-8 are constitutively activated to a certain degree in thymus and spleen, but not in muscle and liver, of one week old TRAF2 KO mice. In TNF/TRAF2 DKO mice, on the other hand, the basal caspase-8 activity is completely suppressed in thymus and spleen, while the basal IKK activity still remained high compared to that in wild-type mice. In addition, caspase-8 substrates such as RIP1 and cFLIP are constitutively cleaved in thymus and spleen, but not in muscle and liver, of TRAF2 KO mice, and these cleavages were completely inhibited in TNF/TRAF2 DKO mice. Functional assays performed in primary MEFs, bone marrow macrophages and T-cells revealed that TRAF2 suppresses basal IKK activity and p100 processing through the NIK-dependent and -independent pathways. Moreover, both the basal and TNFα-induced expression of anti-apoptotic proteins are normal in these primary cells isolated from TNF/TRAF2 DKO embryos and adult mice, yet these cells remain sensitive to TNFα-induced cell death, due to the impaired recruitment of cIAP1/2 to the TNFR1 complex in the absence of TRAF2. Collectively, these data demonstrate that TRAF2 maintains lymphocyte homeostasis by negatively regulating the basal activities of IKK and caspase-8 in thymus and spleen, and that TRAF2 inhibits TNFα-induced cell death by recruiting anti-apoptotic proteins to the TNFR1 complex rather than by activating the NF-κB pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4696. doi:10.1158/1538-7445.AM2011-4696

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