Tumor necrosis factor receptor-associated factor-1 enhances proinflammatory TNF receptor-2 signaling and modifies TNFR1-TNFR2 cooperation.

It has been shown that tumor necrosis factor receptor-2 (TNFR2) stimulation leads to degradation of TNF receptor associated factor-2 (TRAF2) and inhibition of TNFR1-induced activation of NFkappaB and JNK. Here, we show that TRAF1 inhibits TNFR2-induced proteasomal degradation of TRAF2 and relieves TNFR1-induced activation of NFkappaB from the inhibitory effect of TNFR2. TRAF1 co-recruited with TRAF2 to both TNF receptors. Despite lacking an amino-terminal RING/zinc-finger domain, TRAF1 did not interfere with TNFR1-induced activation of JNK and NFkappaB. It is noted that physiological expression levels of TRAF1 enhanced NFkappaB activation and interleukin-8 (IL8) production induced by TNFR2. Thus, TRAF1 shifts the quality of integrated TNFR1-TNFR2 signaling from apoptosis induction to proinflammatory NFkappaB signaling.