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

肿瘤坏死因子受体相关因子(TRAF)蛋白在由肿瘤坏死因子受体(TNFR)和白介素1受体/Toll样受体(IL1R/TLR)家族的受体触发的信号转导中起关键作用。尽管对TRAF2、TRAF3和TRAF6的分子认识有了长足的进步，但TRAF1的生物学功能尚不清楚。已有研究表明，TRAF1调节其他TRAF蛋白的信号特性，从而调节TNFR和TLRs的功能。我们之前确实发现，TRAF1确实不同地影响了不同的肿瘤坏死因子受体对核因子B的激活，从强烈的激活到中性甚至是抑制作用。在拟议的项目中，我们想更详细地调查TRAF1和TNFR的相互作用。我们想要确定使TRAF1能够对TNFR介导的NF？B激活产生不同调节作用的分子机制。此外，我们还将验证TRAF1在肿瘤坏死因子受体和TLR受体调节丝裂原活化蛋白激酶和Akt激活中的可能作用。最后，我们想要扩展我们对TRAF1裂解产物的功能的了解，TRAF1裂解产物作为NF？B信号的全球抑制物。

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.