Wallis Alicia M, Bishop Gail A
Graduate Program in Immunology, Iowa City, Iowa, USA.
Department of Microbiology & Immunology, The University of Iowa, Iowa City, Iowa, USA.
J Leukoc Biol. 2018 Jan 17. doi: 10.1002/JLB.2MIR0817-339RR.
This brief review presents current understanding of how the signaling adapter protein TRAF3 can both induce and block inhibitory signaling pathways in B and T lymphocytes, via association with kinases and phosphatases, and subsequent regulation of their localization within the cell. In B lymphocytes, signaling through the interleukin 6 receptor (IL-6R) induces association of TRAF3 with IL-6R-associated JAK1, to which TRAF3 recruits the phosphatase PTPN22 (protein tyrosine phosphatase number 22) to dephosphorylate JAK1 and STAT3, inhibiting IL-6R signaling. An important biological consequence of this inhibition is restraining the size of the plasma cell compartment, as their differentiation is IL-6 dependent. Similarly, in T lymphocytes, interleukin 2 receptor (IL-2R) signaling recruits TRAF3, which in turn recruits the phosphatase TCPTP (T cell protein tyrosine phosphatase) to dephosphorylate JAK3. The resulting inhibition of IL-2R signaling limits the IL-2-dependent size of the T regulatory cell (Treg) compartment. TRAF3 also inhibits type 1 IFN receptor (IFNαR) signaling to T cells by this mechanism, restraining expression of IFN-stimulated gene expression. In contrast, TRAF3 association with two inhibitors of TCR signaling, C-terminal Src kinase (Csk) and PTPN22, promotes their localization to the cytoplasm, away from the membrane TCR complex. TRAF3 thus enhances TCR signaling and downstream T cell activation. Implications are discussed for these regulatory roles of TRAF3 in lymphocytes, as well as potential future directions.
本简要综述介绍了目前对信号衔接蛋白TRAF3如何通过与激酶和磷酸酶结合，并随后调节它们在细胞内的定位，从而在B淋巴细胞和T淋巴细胞中诱导和阻断抑制性信号通路的理解。在B淋巴细胞中，通过白细胞介素6受体（IL-6R）的信号传导诱导TRAF3与IL-6R相关的JAK1结合，TRAF3将磷酸酶PTPN22（蛋白酪氨酸磷酸酶22）募集到JAK1上，使JAK1和STAT3去磷酸化，从而抑制IL-6R信号传导。这种抑制的一个重要生物学后果是限制浆细胞区室的大小，因为它们的分化依赖于IL-6。同样，在T淋巴细胞中，白细胞介素2受体（IL-2R）信号传导募集TRAF3，TRAF3进而募集磷酸酶TCPTP（T细胞蛋白酪氨酸磷酸酶）使JAK3去磷酸化。由此产生的IL-2R信号传导抑制限制了调节性T细胞（Treg）区室依赖IL-2的大小。TRAF3还通过这种机制抑制1型干扰素受体（IFNαR）向T细胞的信号传导，抑制干扰素刺激基因表达的表达。相反，TRAF3与TCR信号传导的两种抑制剂C末端Src激酶（Csk）和PTPN22结合，促进它们定位于细胞质，远离膜TCR复合物。因此，TRAF3增强了TCR信号传导和下游T细胞活化。文中讨论了TRAF3在淋巴细胞中的这些调节作用的意义以及潜在的未来研究方向。
