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Molecular and Cellular Biology, March 2005, p. 2130-2137, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2130-2137.2005

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

You-Sun Kim,1 Sergei A. Nedospasov,2 and Zheng-gang Liu1*

Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda,1 Basic Research Program, SAIC-Frederick, Inc., and Laboratory of Molecular Immunoregulation, NCI-Frederick, Frederick, Maryland2

Received 20 August 2004/ Returned for modification 17 September 2004/ Accepted 17 December 2004

LIGHT is a member of the tumor necrosis factor (TNF) superfamily, and its function is mediated by at least two receptors, including lymphotoxin ß receptor (LTßR) and herpes simplex virus entry mediator. However, the molecular mechanism of LIGHT signaling mediated by LTßR has not been clearly defined. In this report, we demonstrate that TRAF2 is critical for LIGHT- and LTßR-mediated activation of both the transcription factor NF-{kappa}B and the mitogen-activated protein kinase JNK. In HeLa cells, LIGHT induces NF-{kappa}B 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 I{kappa}B kinase into the LTßR complex. Importantly, while both NF-{kappa}B 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-{kappa}B 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-{kappa}B 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-LTßR signaling.

* Corresponding author. Mailing address: Cell and Cancer Biology Branch, NCI, NIH, Bldg. 10, Rm. 6N105, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-3390. Fax: (301) 402-1997. E-mail: zgliu{at}helix.nih.gov.

Molecular and Cellular Biology, March 2005, p. 2130-2137, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2130-2137.2005




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