Induction of the alternative NF-κB pathway by lymphotoxin αβ (LTαβ) relies on internalization of LTβ receptor.

Several tumor necrosis factor receptor (TNFR) family members activate both the classical and the alternative NF-kappa B pathways. However, how a single receptor engages these two distinct pathways is still poorly understood. Using lymphotoxin beta receptor (LT beta R) as a prototype, we showed that activation of the alternative, but not the classical, NF-kappa B pathway relied on internalization of the receptor. Further molecular analyses revealed a specific cytosolic region of LT beta R essential for its internalization, TRAF3 recruitment, and p100 processing. Interestingly, we found that dynamin-dependent, but clathrin-independent, internalization of LT beta R appeared to be required for the activation of the alternative, but not the classical, NF-kappa B pathway. In vivo, ligand-induced internalization of LT beta R in mesenteric lymph node stromal cells correlated with induction of alternative NF-kappa B target genes. Thus, our data shed light on LT beta R cellular trafficking as a process required for specific biological functions of NF-kappa B.