Functions of TRAF1 in tumor necrosis factor (TNF) receptor signaling

TNF受体相关因子（TRAF）蛋白在由TNF受体（TNFR）和白细胞介素-1受体/Toll样受体（IL 1 R/TLR）家族的受体触发的信号级联中起关键作用。尽管对TRAF 2、3和6的分子理解有了相当大的进展，但TRAF 1的生物学功能还不清楚。研究表明，TRAF 1调节其他TRAF蛋白的信号传导特性，从而调节TNFR和TLR的功能。我们以前确实发现TRAF 1通过不同的TNF受体对NF B的激活有不同的影响，从强激活到中性甚至抑制作用。在拟议的项目中，我们希望更详细地调查TRAF 1和TNFRs的相互作用。我们希望确定TRAF 1对TNFR介导的NF B激活产生不同调节作用的分子机制。此外，我们将验证TRAF 1在调节促分裂原活化蛋白激酶和TNF受体以及TLR受体激活Akt中的可能作用。最后，我们希望扩展我们对TRAF 1裂解产物功能的了解，该产物作为NF B信号传导的全局抑制剂。

TNF receptor associated factor (TRAF) proteins play a pivotal role in signaling cascades, triggered by receptors of the TNF receptor (TNFR) and Interleukin-1 receptor/Toll-like receptor (IL1R/TLR) families. Although there was considerable progress in the molecular understanding of TRAF2, 3 and 6, the biological functions of TRAF1 are poorly defined. It has been shown that TRAF1 regulates signaling properties of other TRAF proteins and thus functions of TNFRs and TLRs. We did previously find that TRAF1 does differentially affect NF¿B activation by various TNF receptors, ranging from strong activation to neutral or even inhibiting effects. In the proposed project, we would like to investigate in more detail the interplay of TRAF1 and TNFRs. We want to define the molecular mechanisms that enable TRAF1 to elicit its diverse regulatory effects on TNFR-mediated NF¿B activation. Moreover, we will verify a possible role of TRAF1 in regulation of mitogen-activated protein kinases and Akt activation by TNF receptors, as well as TLR receptors. Finally, we want to extend our knowledge on the functions of a TRAF1 cleavage product that acts as a global inhibitor of NF¿B signaling.