Coordination between NF-κB family members p50 and p52 is essential for mediating LTβR signals in the development and organization of secondary lymphoid tissues

James C. Lo, Soumen Basak, Ethan S. James, Raechel S. Quiambo, Marcus C. Kinsella, Maria Luisa Alegre, Falk Weih, Guido Franzoso, Alexander Hoffmann, Yang Xin Fu

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Recent studies revealed that the lymphotoxin/lymphotoxin beta receptor (LT)/LTβR system activates the noncanonical nuclear factor-κB (NF-κB) signaling pathway involving I kappa B kinase 1/I kappa B kinase α (IKK1/IKKα) and NF-κB-inducing kinase (NIK) to direct processing of the nfκb2 protein p100 to yield RelB:p52 complexes. Despite the biochemical evidence, LT-, RelB-, p52-deficient mice show discrepant phenotypes. We now demonstrate that p105/p50 also constitutes an important pathway for LTβR signaling. Our studies revealed that mice deficient in either p50 or p52 have defects in the formation of inguinal lymph nodes (LNs), but that the complete defect in lymph node formation and splenicmicroarchitecture seen in LT-deficient mice is recapitulated only in mice deficient in both p50 and p52. Biochemically, we find not only that both p50- and p52-containing NF-κB activities are induced by LTβR signaling, but that the induction of NF-κB-containing complexes by LTβR engagement is perturbed in single knockouts. Importantly, the LTβR can additionally activate the less well-characterized p52:RelA and p50:RelB pathways, which play pivotal roles in vivo for the development and organization of lymphoid structures. Our genetic, cellular, and molecular evidence points toward a model of LT-mediated NF-κB regulation in which p105/p50 and p100/p52 have distinct and coordinating molecular specificities but differ in the upstream signaling pathways that regulate them.

Original languageEnglish (US)
Pages (from-to)1048-1055
Number of pages8
JournalBlood
Volume107
Issue number3
DOIs
StatePublished - Feb 1 2006

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Lo, J. C., Basak, S., James, E. S., Quiambo, R. S., Kinsella, M. C., Alegre, M. L., Weih, F., Franzoso, G., Hoffmann, A., & Fu, Y. X. (2006). Coordination between NF-κB family members p50 and p52 is essential for mediating LTβR signals in the development and organization of secondary lymphoid tissues. Blood, 107(3), 1048-1055. https://doi.org/10.1182/blood-2005-06-2452