TMED2 Potentiates Cellular IFN Responses to DNA Viruses by Reinforcing MITA Dimerization and Facilitating Its Trafficking
TMED2 Potentiates Cellular IFN Responses to DNA Viruses by Reinforcing MITA Dimerization and Facilitating Its Trafficking
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TMED2 通过加强 MITA 二聚化并促进其运输来增强细胞 IFN 对 DNA 病毒的反应
DOI：
10.1016/j.celrep.2018.11.048
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发表时间：
2018-12-11
期刊：
影响因子：
8.8
通讯作者：
Liu, Yu
中科院分区：
文献类型：
--
作者：
Sun, Ming-Shun;Zhang, Jie;Liu, Yu
IRF 3激活介体（Mediator of IRF 3 activation，MITA），也称为干扰素基因刺激物（stimulator of interferon genes，STING），在针对胞质dsDNA的先天免疫应答中起着至关重要的作用。MITA从ER运输到核周囊泡是其激活下游分子所必需的，这导致干扰素和促炎细胞因子的产生。然而，MITA激活的确切机制仍然难以捉摸。在这里，我们报告，跨膜emp 24蛋白转运域2（TMED 2）加强DNA病毒诱导的MITA信号。TMED 2的抑制或缺失显著损害HSV-1感染后I型IFN的产生。TMED 2缺陷细胞比对照细胞具有更大的HSV-1负荷。在机制上，TMED 2仅在病毒刺激时与MITA结合，并且该过程通过加强其二聚化和促进其运输来增强MITA活化。这些发现表明TMED 2在细胞对DNA病毒的IFN应答中起重要作用。
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.