cDNA cloning and functional analysis of a signal transducer, TRAF5

1.我们发现TRAF2和TRAF5与CD27和CD3O相互作用，并通过这些受体参与核因子-kappaB的激活。我们还测定了CD27和CD3O与TRAF2和TRAF5.2的结合域。最近，核因子-kappaB激酶(NUK)被发现并激活了1kappaB激酶复合体的两个亚基IKKalpha和IKKbeta，这两个亚基都直接磷酸化了IkappaB。我们证明，当Nik激活IKKalpha和IKK3b时，Mekki优先激活IKKbeta。我们发现，在肿瘤坏死因子作用下，TRAF2与凋亡调节激酶1(ASK1)相互作用，而ASK1是TRAF2介导的TNK/SAPK激活所必需的。为了确定TRAF5在体内的功能，我们建立了TRAF5缺陷小鼠。尽管TRAF5基因缺陷小鼠不存在肿瘤坏死因子、CD27和CD4O介导的NF-kappaB或JNK/SAPK活化缺陷，但CD4O和CD27介导的淋巴细胞活化受到损害。这些结果表明，TRAF5具有一种新的功能，该功能不依赖于核因子-kappaB或JNK/SAPK的激活。

1. We demonstrated that TRAF2 and TRAF5 interact with CD27 and CD3O, and are involved in NF-kappaB activation by these receptors. We also determined the binding domain of CD27 and CD3O for TRAF2 and TRAF5.2. Recently, NF-kappaB kinase (NIK) was identified and has been shown to activate two subunits of the 1kappaB kinase complex, IKKalpha and IKKbeta, both of which directly phosphorylate IkappaBs. We demonstrated that while NIK activates IKKalpha and IKK3b comparably, MEKKI preferentially activates IKKbeta.3. We showed that upon TNF treatment, TRAF2 interacts with apoptosis-regulating kinase 1 (ASK 1) and ASK1 is essential for TRAF2-mediated TNK/SAPK activation.4. To determined the function of TRAF5 in vivo, we generated TRAF5-deficient mice. Despite of no defect of TNF-, CD27-, or CD4O-mediated activation of NF-kappaB or JNK/SAPK in TRAF5-deficient mice, CD4O- and CD27-mediated lymphocyte activation were impaired. These results suggest that a novel function of TRAF5, which is independent on activation of NF-kappaB or JNK/SAPK.