TRAF2 plays a key, nonredundant role in LIGHT-lymphotoxin β receptor signaling

LIGHT is a member of the tumor necrosis factor (TNF) superfamily, and its function is mediated by at least two receptors, including lymphotoxin P receptor (LTbetaR) and herpes simplex virus entry mediator. However, the molecular mechanism of LIGHT signaling mediated by LTbetaR has not been clearly defined. In this report, we demonstrate that TRAF2 is critical for LIGHT- and LTbetaR-mediated activation of both the transcription factor NF-kappaB and the mitogen-activated protein kinase JNK. In HeLa cells, LIGHT induces NF-kappaB and JNK activation, which can be blocked by the dominant negative mutant of TRAF2. In these cells, LIGHT causes the recruitment of TRAF2, TRAF3, and IkappaB kinase into the LTbetaR complex. Importantly, while both NF-kappaB and JNK are activated by LIGHT in wild-type mouse embryonic fibroblasts, no activation of either of these two pathways is observed in TRAF2 null fibroblasts. However, LIGHT-induced NF-kappaB and JNK activation can be restored by ectopic expression of TRAF2 in TRAF(-/-) cells. Interestingly, in contrast to TNF signaling, the activation of both NF-kappaB and JNK by LIGHT was normal in RIP-/- and TRAF5(-/-) cells. Taken together, our data demonstrate that TRAF2, an important effector molecule of TNF signaling, plays a critical, nonredundant role in LIGHT-LTbetaR signaling.