MmuEX0048696 @ mm10

The noncanonical nuclear factor _B (ncNF_B) pathway regulates the expression of chemokines required for secondary lymphoid organ formation and thus plays a pivotal role in adaptive immunity. Whereas ncNF_B signaling has been well described in stromal cells and B cells, its role and regulation in T cells remain largely unexplored. ncNF_B activity critically depends on the upstream NF_B-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. The authors show that T cell-specific and activation-dependent alternative splicing generates a Traf3 isoform lacking exon 8 (Traf3DE8) (HsaEX0066805) that, in contrast to the full-length protein, activates ncNF_B signaling. Traf3DE8 disrupts the NIK-Traf3-Traf2 complex and allows accumulation of NIK to initiate ncNF_B signaling in activated T cells.