title: Activation-induced tumor necrosis factor receptor-associated factor 3 (Traf3) alternative splicing controls the noncanonical nuclear factor κB pathway and chemokine expression in human T cells.
abstract: The noncanonical nuclear factor κB (ncNFκB) pathway regulates the expression of chemokines required for secondary lymphoid organ formation and thus plays a pivotal role in adaptive immunity. Whereas ncNFκB signaling has been well described in stromal cells and B cells, its role and regulation in T cells remain largely unexplored. ncNFκB activity critically depends on the upstream NFκB-inducing kinase (NIK). NIK expression is negatively regulated by the full-length isoform of TNF receptor-associated factor 3 (Traf3) as formation of a NIK-Traf3-Traf2 complex targets NIK for degradation. Here we show that T cell-specific and activation-dependent alternative splicing generates a Traf3 isoform lacking exon 8 (Traf3DE8) that, in contrast to the full-length protein, activates ncNFκB signaling. Traf3DE8 disrupts the NIK-Traf3-Traf2 complex and allows accumulation of NIK to initiate ncNFκB signaling in activated T cells. ncNFκB activity results in expression of several chemokines, among them B cell chemoattractant (CxCL13), both in a model T cell line and in primary human CD4(+) T cells. Because CxCL13 plays an important role in B cell migration and activation, our data suggest an involvement and provide a mechanistic basis for Traf3 alternative splicing and ncNFκB activation in contributing to T cell-dependent adaptive immunity.
authors.affiliation: From the Philipps-University Marburg, Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35032 Marburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Michel
authors.forename: Ilka
authors.initials: I
authors.lastname: Wilhelmi
authors.forename: Astrid-Solveig
authors.initials: AS
authors.lastname: Schultz
authors.forename: Marco
authors.initials: M
authors.lastname: Preussner
authors.forename: Florian
authors.initials: F
authors.lastname: Heyd
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology*; D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D054382:Chemokine CXCL13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D054382:Chemokine CXCL13; D016328:NF-kappa B; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase; C110663:CXCL13 protein, human; C090656:TRAF3 protein, human
keywords: Alternative Splicing; Nuclear Factor κB (NFκB); RNA Splicing; T Cell; TRAF