AN INTACT ZINC RING FINGER IS REQUIRED FOR TUMOR-NECROSIS-FACTOR RECEPTOR-ASSOCIATED FACTOR-MEDIATED NUCLEAR FACTOR-KAPPA-B ACTIVATION BUT IS DISPENSABLE FOR C-JUN N-TERMINAL KINASE SIGNALING

The diverse biological effects of the tumor necrosis factor (TNF) rece ptor superfamily are believed to be mediated in part through TNF recep tor-associated factors (TRAFs), a family of cytoplasmic adaptor protei ns which can activate intracellular signaling pathways, including the nuclear factor-kappa B (NF-kappa B) and c-Jun N-terminal kinase (JNK) pathways. TRAFs 2, 5, and 6 strongly activate both pathways when overe xpressed; however, TRAF 3 (a close homologue of TRAF 5) does not signi ficantly activate either pathway. The current study addresses the stru ctural basis for this difference by substituting corresponding domains of TRAF 5 into TRAF 3 and testing activation of both pathways. A smal l region of TRAF 5 (the first zinc finger and 10 residues of the secon d zinc finger) is sufficient to convert TRAF 3 into an activator of bo th pathways. Also, an intact zinc ring finger is required for NF-kappa B activation but not JNK activation. In agreement with this finding, TRAF 2A, a TRAF 2 splice variant with an altered ring finger, is a spe cific activator of JNK. These findings suggest that different domains of TRAFs may be involved in NF-kappa B and JNK signaling. Also, altern ative splicing of TRAFs may represent a novel mechanism whereby TNF fa mily receptors can mediate distinct downstream effects in different ti ssues.