Human Cytomegalovirus Encoded miR-US25-1-5p Attenuates CD147/EMMPRIN-Mediated Early Antiviral Response.
Human Cytomegalovirus Encoded miR-US25-1-5p Attenuates CD147/EMMPRIN-Mediated Early Antiviral Response.
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人巨细胞病毒编码的 miR-US25-1-5p 减弱 CD147/EMMPRIN 介导的早期抗病毒反应
DOI：
10.3390/v9120365
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发表时间：
2017-12-01
期刊：
影响因子：
--
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Chen J;Xia S;Yang X;Chen H;Li F;Liu F;Chen Z
细胞受体介导的信号通路在人巨细胞病毒(HCMV)感染的初始免疫应答中起着关键作用。然而，I型跨膜糖蛋白CD147/EMMPRIN(细胞外基质金属蛋白酶诱导物)在抗病毒应答中的作用尚不清楚。在这里，我们证明了CD147的特异性敲除显著降低了巨细胞病毒诱导的核因子-κB和干扰素-β(干扰素-β)的激活，这有助于细胞抗病毒反应。接下来，我们证实了HCMV编码的miR-US25-1-5p可以靶向CD147的3‘非翻译区，从而在低感染复数(MOI)下促进HCMV的裂解繁殖。作为CD147配体和促炎细胞因子的亲环素A(CyPA)的表达和分泌在HCMV刺激下上调。最后，我们证实CD147通过细胞外调节蛋白激酶/NF-κB轴信号通路介导了巨细胞病毒触发的抗病毒信号转导。这些发现揭示了HCMV通过其编码的microRNA靶向跨膜糖蛋白CD147来逃避抗病毒天然免疫的重要机制，以及由于促炎细胞因子CyPA的分泌而导致HCMV炎性疾病的潜在原因。
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.
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