CD27 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on T, B, and NK cells. The signal via CD27 plays pivotal roles in T-T and T-B cell interactions. Here we demonstrate that overexpression of CD27 activates NF-B and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). Deletion analysis of the cytoplasmic domain of CD27revealed that the C-terminal PIQEDYR motif was indispensable for both NF-B and SAPK/JNK activation and was also required for the interaction with TNF receptorassociated factor (TRAF) 2 and TRAF5, both of which have been implicated in NF-B activation by members of the TNF-R superfamily. Co-transfection of a dominant negative TRAF2 or TRAF5 blocked NF-B and SAPK/ JNK activation induced by CD27. Recently, a TRAF2-interacting kinase has been identified, termed NF-Binducing kinase (NIK). A kinase-inactive mutant NIK blocked CD27-, TRAF2-, and TRAF5-mediated NF-B and SAPK/JNK activation. These results indicate that TRAF2 and TRAF5 are involved in NF-B and SAPK/ JNK activation by CD27, and NIK is a common downstream kinase of TRAF2 and TRAF5 for NF-B and SAPK/JNK activation.
CD27 is a member of the tumor necrosis factor receptor (TNF-R)1 superfamily and is expressed on T, B, and NK cells as a disulfide-linked homodimer (1). CD27 ligand (CD70) belongs to the TNF superfamily and is expressed on the surface of activated T and B cells. Cross-linking of CD27 along with a suboptimal dose of phytohemagglutinin, phorbol 12-myristate 13-acetate, anti-CD2, or anti-CD3 antibodies resulted in vigorous proliferation of T cells, indicating that CD27 transmits a co-stimulatory signal in T cells (2). On the other hand, ligation of CD27 on B cells enhanced IgG production (3). These studies implicated the important roles of CD27/CD70 interaction in immunoregulation through T-T and T-B cell interactions. A recent report also demonstrated a critical role of CD27/CD70 interaction in T cell development (4). Although biological function of CD27/CD70 interaction has been extensively investigated, the mechanism by which CD27 transmits the signal has been largely unknown, except for a previous study, which demonstrated involvement of the protein tyrosine kinase cascade (2).TNF receptor-associated factors (TRAFs) have emerged as signal transducers for some members of the TNF-R superfamily (5-10). All TRAFs, except for TRAF1, are composed of Nterminal zinc RING finger, multiple zinc fingers, coiled-coil, and C-terminal receptor binding (TRAF) domains (5, 6, 9 -11). Whereas an N-terminal RING finger domain of TRAF2, TRAF5, and TRAF6 is responsible for NF-B activation, the TRAF and coiled-coil domains are required for homo-and heterodimerization and receptor association (5,6,9,10,12). With the exception of TRAF4, all other TRAFs have been shown to interact directly with the non-death domain receptors, CD30, CD40, TNFR80, lymphotoxin-R (LT-R), and interleukin-1R (9,10,(12)(13)(14)(15)(16). TRAF2 has been shown to interact indirectly with death domain receptors, TNFR60 and death r...