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