Induction of the Alternative NF-B Pathway by Lymphotoxin (LT) Relies on Internalization of LT Receptor†

Several tumor necrosis factor receptor (TNFR) family members activate both the classical and the alter-native NF-B pathways. However, how a single receptor engages these two distinct pathways is still poorly understood. Using lymphotoxin receptor (LTR) as a prototype, we showed that activation of the alternative, but not the classical, NF-B pathway relied on internalization of the receptor. Further molecular analyses revealed a specific cytosolic region of LTR essential for its internalization, TRAF3 recruitment, and p100 processing. Interestingly, we found that dynamin-dependent, but clathrin-independent, internalization of LTR appeared to be required for the activation of the alternative, but not the classical, NF-B pathway. In vivo, ligand-induced internalization of LTR in mesenteric lymph node stromal cells correlated with induction of alternative NF-B target genes. Thus, our data shed light on LTR cellular trafficking as a process required for specific biological functions of NF-B. The tumor necrosis factor receptor (TNFR)/tumor necrosis factor ligand (TNFL) superfamily forms a complex network of cytokines and receptors that are important for biological func-tions ranging from cell homeostasis and inflammation to lym-phoid organ development (20). This family is subdivided ac