State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430072, China.
Cell Rep. 2018 Dec 11;25(11):3086-3098.e3. doi: 10.1016/j.celrep.2018.11.048.
Mediator of IRF3 activation (MITA), also known as stimulator of interferon genes (STING), plays a vital role in the innate immune responses to cytosolic dsDNA. The trafficking of MITA from the ER to perinuclear vesicles is necessary for its activation of the downstream molecules, which lead to the production of interferons and pro-inflammatory cytokines. However, the exact mechanism of MITA activation remains elusive. Here, we report that transmembrane emp24 protein transport domain containing 2 (TMED2) potentiates DNA virus-induced MITA signaling. The suppression or deletion of TMED2 markedly impairs the production of type I IFNs upon HSV-1 infection. TMED2-deficient cells harbor greater HSV-1 load than the control cells. Mechanistically, TMED2 associates with MITA only upon viral stimulation, and this process potentiates MITA activation by reinforcing its dimerization and facilitating its trafficking. These findings suggest an essential role of TMED2 in cellular IFN responses to DNA viruses.
干扰素调节因子 3 激活介体（MITA），也称为干扰素基因刺激物（STING），在细胞质双链 DNA 的先天免疫反应中起着至关重要的作用。MITA 从内质网到核周小泡的运输对于其下游分子的激活是必要的，这导致干扰素和促炎细胞因子的产生。然而，MITA 激活的确切机制仍不清楚。在这里，我们报告跨膜 emp24 蛋白运输结构域包含 2（TMED2）增强了 DNA 病毒诱导的 MITA 信号。TMED2 的抑制或缺失显著损害了 HSV-1 感染后 I 型 IFNs 的产生。TMED2 缺陷细胞比对照细胞携带更多的 HSV-1 负荷。在机制上，只有在病毒刺激时，TMED2 才与 MITA 结合，这一过程通过加强 MITA 的二聚化和促进其运输来增强 MITA 的激活。这些发现表明 TMED2 在细胞对 DNA 病毒的 IFN 反应中起着重要作用。
