National Translational Science Center for Molecular Medicine, Xi'an 710032, China.
Cell Engineering Research Center & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China.
Viruses. 2017 Dec 1;9(12):365. doi: 10.3390/v9120365.
Cellular receptor-mediated signaling pathways play critical roles during the initial immune response to Human Cytomegalovirus (HCMV) infection. However, the involvement of type-I transmembrane glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in the antiviral response to HCMV infection is still unknown. Here, we demonstrated the specific knockdown of CD147 significantly decreased HCMV-induced activation of NF-κB and Interferon-beta (IFN-β), which contribute to the cellular antiviral responses. Next, we confirmed that HCMV-encoded miR-US25-1-5p could target the 3' UTR (Untranslated Region) of CD147 mRNA, and thus facilitate HCMV lytic propagation at a low multiplicity of infection (MOI). The expression and secretion of Cyclophilin A (sCyPA), as a ligand for CD147 and a proinflammatory cytokine, were up-regulated in response to HCMV stimuli. Finally, we confirmed that CD147 mediated HCMV-triggered antiviral signaling via the sCyPA-CD147-ERK (extracellular regulated protein kinases)/NF-κB axis signaling pathway. These findings reveal an important HCMV mechanism for evading antiviral innate immunity through its encoded microRNA by targeting transmembrane glycoprotein CD147, and a potential cause of HCMV inflammatory disorders due to the secretion of proinflammatory cytokine CyPA.
细胞受体介导的信号通路在人类巨细胞病毒（HCMV）感染的初始免疫反应中发挥着关键作用。然而，Ⅰ型跨膜糖蛋白 CD147/EMMPRIN（细胞外基质金属蛋白酶诱导剂）在 HCMV 感染的抗病毒反应中的参与仍然未知。在这里，我们证明了 CD147 的特异性敲低显著降低了 HCMV 诱导的 NF-κB 和干扰素-β（IFN-β）的激活，这有助于细胞的抗病毒反应。接下来，我们证实 HCMV 编码的 miR-US25-1-5p 可以靶向 CD147 mRNA 的 3'UTR（非翻译区），从而在低感染复数（MOI）下促进 HCMV 的裂解增殖。细胞环孢素 A（sCyPA）的表达和分泌作为 CD147 的配体和促炎细胞因子，对 HCMV 刺激有反应而上调。最后，我们证实 CD147 通过 sCyPA-CD147-ERK（细胞外调节蛋白激酶）/NF-κB 信号通路介导 HCMV 触发的抗病毒信号。这些发现揭示了 HCMV 通过其编码的 microRNA 靶向跨膜糖蛋白 CD147 逃避抗病毒先天免疫的重要机制，以及由于促炎细胞因子 CyPA 的分泌导致 HCMV 炎症性疾病的潜在原因。
