TRAF2 Plays a Key, Nonredundant Role in LIGHT-Lymphotoxin β Receptor Signaling

Abstract

LIGHT is a member of the tumor necrosis factor (TNF) superfamily, and its function is mediated by at least two receptors, including lymphotoxin β receptor (LTβR) and herpes simplex virus entry mediator. However, the molecular mechanism of LIGHT signaling mediated by LTβR has not been clearly defined. In this report, we demonstrate that TRAF2 is critical for LIGHT- and LTβR-mediated activation of both the transcription factor NF-κB and the mitogen-activated protein kinase JNK. In HeLa cells, LIGHT induces NF-κB 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 IκB kinase into the LTβR complex. Importantly, while both NF-κB 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-κB and JNK activation can be restored by ectopic expression of TRAF2 in TRAF2^−/− cells. Interestingly, in contrast to TNF signaling, the activation of both NF-κB 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-LTβR signaling.

ACKNOWLEDGMENTS

We thank W. C. Yeh and T. W. Mak for the TRAF2^−/− fibroblasts, M. Kelliher for RIP^−/− fibroblasts, H. Nakano for TRAF5^−/− fibroblasts, and J. Browning for the agonistic anti-LTβR antibody. We thank M. Drutskaya for help with MEF preparations. We are also grateful to Swati Choksi for her critical reading of the manuscript.

S.A.N. is funded in part with U.S. Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400.

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