Activation-induced Tumor Necrosis Factor Receptorassociated Factor 3 ( Traf3) Alternative Splicing Controls the Noncanonical Nuclear Factor kappa B Pathway and Chemokine Expression in Human T Cells

作者：Michel Monika; Wilhelmi Ilka; Schultz Astrid Solveig; Preussner Marco; Heyd Florian^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(19): 13651-13660.

DOI：10.1074/jbc.M113.526269

• Alternative Splicing
• Nuclear Factor B (NFB)
• RNA Splicing
• T Cell
• TRAF

Background: Many pre-mRNAs are alternatively spliced upon T cell activation, but functional implications remain largely unexplored. Results: Alternative splicing of the signaling adaptor Traf3 controls expression of effector proteins in activated T cells. Conclusion: Cell type-specific and activation-dependent alternative splicing regulates signaling and gene expression in T cells. Significance: Alternative splicing plays a fundamental role in regulating functionality upon T cell activation. %26lt;br%26gt;The noncanonical nuclear factor B (ncNFB) pathway regulates the expression of chemokines required for secondary lymphoid organ formation and thus plays a pivotal role in adaptive immunity. Whereas ncNFB signaling has been well described in stromal cells and B cells, its role and regulation in T cells remain largely unexplored. ncNFB activity critically depends on the upstream NFB-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 ncNFB signaling. Traf3DE8 disrupts the NIK-Traf3-Traf2 complex and allows accumulation of NIK to initiate ncNFB signaling in activated T cells. ncNFB 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 ncNFB activation in contributing to T cell-dependent adaptive immunity.

• 出版日期2014-5-9