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TRAF2 Plays a Key, Non-redundant Role in LIGHT/Lymphotoxin β Receptor Signaling
umor necrosis factor (TNF)–related cytokines play critical roles in inflammatory and immune responses. Acting through their specific cellular receptors, these cytokines initiate diverse signaling pathways that regulate cell death, survival, and differentiation. LIGHT is one member of the TNF superfamily, and its receptor, lymphotoxin β receptor (LTβR), belongs to the TNF-receptor superfamily. LTβR is a key mediator for development, organization, and differentiation of lymphoid tissue and is expressed on most types of cells including fibroblasts and epithelial and myeloid lineages. The pathway involving LIGHT/LTβR–mediated activation of transcription factor nuclear factor-κB (NF-κB) is a major pathway responsible for LIGHT and LTβR’s diverse biological functions. Previous studies have suggested that TNF receptor–associated factors, such as TRAF3 and TRAF5, are key mediators of LTβR signaling, particularly in the activation of the NF-κB pathway. We found that LIGHT activates both NF-κB and c-JUN N-terminal kinase (JNK), to control the life and death of a cell. NF-κB regulates the expression of genes crucial to innate and adaptive immune responses, cell growth, and apoptosis. JNK, also known as stress-activated kinase (SAPK), is activated by many apoptosis-inducing stimuli and is thought to be an important apoptotic mediator. In addition, JNK activation is involved in many other biological processes, such as cell proliferation, embryogenesis, and immune responses. We demonstrated that TNF receptor–associated factor-2 (TRAF2) has an essential, non-redundant role in LIGHT/LTβR–mediated activation of both NF-κB and JNK. In HeLa cells, LIGHT induces NF-κB and JNK activation, which can be blocked by the dominant-negative mutant of TRAF2. We found that LIGHT treatment results in the recruitment of TRAF2, TRAF3, and IKK (a protein kinase) to the LTβR signaling complex. Although both NF-κB and JNK pathways are activated by LIGHT in wild-type mouse embryonic fibroblasts (MEFs), neither of these two pathways was activated in TRAF2-null fibroblasts. More importantly, 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 in TNF signaling, plays a critical, non-redundant role in LIGHT-LTβR signaling. Our study documents that LIGHT is a potent activator of the MAP kinase JNK pathway. As a key modulator of the transcription factor AP-1, JNK may play a critical role in LIGHT-mediated cellular responses, in particular those involved in the development and maintenance of the lymphoid tissues. Although our current work has made progress in understanding mechanisms of LIGHT/LTβR signaling, much remains to be done. For instance, it will be important to determine how NF-κB and JNK pathways are specifically regulated by TRAF2 in response to LIGHT treatment and to discern the respective role of these two pathways in LIGHT-mediated cellular responses. Meeting these challenges will help us to better understand the physiological functions of LIGHT and LTβR.
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