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

Mol Cell Biol. 2011 Nov;31(21):4319-34. doi: 10.1128/MCB.05033-11. Epub 2011 Sep 6.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Biological Transport, Active
  • Clathrin Heavy Chains / antagonists & inhibitors
  • Clathrin Heavy Chains / genetics
  • Clathrin Heavy Chains / metabolism
  • Cytosol / metabolism
  • Dynamin II / antagonists & inhibitors
  • Dynamin II / genetics
  • Dynamin II / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lymphotoxin alpha1, beta2 Heterotrimer / metabolism*
  • Lymphotoxin beta Receptor / chemistry
  • Lymphotoxin beta Receptor / deficiency
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • NF-kappa B / metabolism*
  • NF-kappa B p52 Subunit / metabolism
  • NF-kappaB-Inducing Kinase
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • TNF Receptor-Associated Factor 3 / metabolism
  • Transcription Factor RelB / deficiency
  • Transcription Factor RelB / genetics
  • Transcription Factor RelB / metabolism

Substances

  • Lymphotoxin alpha1, beta2 Heterotrimer
  • Lymphotoxin beta Receptor
  • NF-kappa B
  • NF-kappa B p52 Subunit
  • RNA, Small Interfering
  • Relb protein, mouse
  • TNF Receptor-Associated Factor 3
  • Clathrin Heavy Chains
  • Transcription Factor RelB
  • Protein Serine-Threonine Kinases
  • Dynamin II