MDA5 Induces a Stronger Interferon Response than RIG-I to GCRV Infection through a Mechanism Involving the Phosphorylation and Dimerization of IRF3 and IRF7 in CIK Cells.
MDA5 Induces a Stronger Interferon Response than RIG-I to GCRV Infection through a Mechanism Involving the Phosphorylation and Dimerization of IRF3 and IRF7 in CIK Cells.
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MDA5 通过涉及 CIK 细胞中 IRF3 和 IRF7 磷酸化和二聚化的机制，对 GCRV 感染诱导比 RIG-I 更强的干扰素反应
DOI：
10.3389/fimmu.2017.00189
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发表时间：
2017
影响因子：
7.3
通讯作者：
Su J
中科院分区：
文献类型：
--
作者：
Wan Q;Yang C;Rao Y;Liao Z;Su J
维甲酸诱导基因I（RIG-I）和黑色素瘤分化相关基因5（MDA5）是触发干扰素（IFN）产生的关键胞质感受器。尽管它们的识别功能已得到明确鉴定，但其在下游信号转导中的独特作用仍有待阐明。在此，我们报道了草鱼（Ctenopharyngodon idella）MDA5（CiMDA5）和CiRIG-I在草鱼呼肠孤病毒（GCRV）感染草鱼肾（CIK）细胞系时，对多种干扰素产生的不同影响。在CIK细胞中，草鱼IFN1（CiIFN1）和CiIFN3表达相对较高，而CiIFN2和CiIFN4表达相对较低。GCRV感染后，CiMDA5比CiRIG-I诱导更广泛的I型干扰素应答。进一步研究表明，在GCRV感染或聚肌胞苷酸（poly(I:C)）刺激后，CiMDA5和CiRIG-I均促进草鱼干扰素调节因子（IRF）3（CiIRF3）和CiIRF7的表达及总磷酸化水平。然而，不同之处在于CiRIG-I降低了CiIRF7的苏氨酸磷酸化水平。因此，CiMDA5增强了CiIRF3与CiIRF7的异源二聚化以及CiIRF7的同源二聚化，而CiRIG-I促进异源二聚化但减弱了CiIRF7的同源二聚化。此外，本研究表明，在GCRV感染下，CiIRF3与CiIRF7的异源二聚体以及CiIRF7的同源二聚体比CiIRF3同源二聚体能够诱导更广泛的I型干扰素应答。另外，CiMDA5比CiRIG-I对GCRV感染诱导更强的II型干扰素（IFN-II）应答。综上所述，这些结果表明，CiMDA5通过对CiIRF3和CiIRF7磷酸化及二聚化的差异调节，在对GCRV感染的干扰素应答中比CiRIG-I发挥更重要的作用。
Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are critical cytosolic sensors that trigger the production of interferons (IFNs). Though their recognition functions are well identified, their unique roles in the downstream signal transduction remain to be elucidated. Herein, we report the differential effect between grass carp (Ctenopharyngodon idella) MDA5 (CiMDA5) and CiRIG-I on the production of various IFNs upon grass carp reovirus (GCRV) infection in C. idella kidney (CIK) cell line. In CIK cells, grass carp IFN1 (CiIFN1) and CiIFN3 are relatively highly expressed while CiIFN2 and CiIFN4 are relatively slightly expressed. Following GCRV infection, CiMDA5 induces a more extensive type I IFN response than CiRIG-I. Further investigation reveals that both CiMDA5 and CiRIG-I facilitate the expression and total phosphorylation levels of grass carp IFN regulatory factor (IRF) 3 (CiIRF3) and CiIRF7 upon GCRV infection or poly(I:C) stimulation. However, the difference is that CiRIG-I decreases the threonine phosphorylation level of CiIRF7. As a consequence, CiMDA5 enhances the heterodimerization of CiIRF3 and CiIRF7 and homodimerization of CiIRF7, whereas CiRIG-I facilitates the heterodimerization but attenuates homodimerization of CiIRF7. Moreover, the present study suggests that CiIRF3 and CiIRF7 heterodimers and CiIRF7 homodimers are able to induce more extensive IFN-I responses than CiIRF3 homodimers under GCRV infection. Additionally, CiMDA5 induces a stronger type II IFN (IFN-II) response against GCRV infection than CiRIG-I. Collectively, these results demonstrate that CiMDA5 plays a more potent role than CiRIG-I in IFN response to GCRV infection through differentially regulating the phosphorylation and dimerization of CiIRF3 and CiIRF7.