Induction of the Alternative NF-kappa B Pathway by Lymphotoxin alpha beta (LT alpha beta) Relies on Internalization of LT beta 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.