pro-survival (or in certain conditions, pro-apoptotic) signaling, playing a central role in healthy inflammatory response, but also in inflammatory disease and cancer. Binding has long been thought to be sufficient for receptor activation, however we have recently published evidence that TNFR1 undergoes a conformational change upon formation of an oligomeric network, suggesting that the ligand binds and arranges pre-formed receptor dimers into a highly organized lattice. Because lymphotoxin and TNF share the same receptors, their individual roles in signaling are not clearly delineated. We have discovered that oxidative stress abolishes bioactivity of lymphotoxin by causing sulfoxidation of several methionine residues that are absent in the homologous TNF sequence. We have shown in a recent publication that the lymphotoxin-TNFR1 binding is stabilized by Met120 of lymphotoxin through a sulfuraromatic interaction and proposed that it may be disrupted by oxidation. However, immunoprecipitation shows that while ligand induced signaling is ablated after oxidative modification, ligand-receptor binding is not. This key distinction where the potency, but not the binding affinity of lymphotoxin is inhibited by oxidative stress, may play a key regulatory role in the highly complex lymphotoxin, TNF, TNFR1, and TNFR2 signaling system in which ligands and receptors cooperate and compete to dictate a specific signaling outcome, especially in the cases of inflamed or cancerous tissue, where the extracellular environment is strongly oxidative.
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