Abstract
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.
Highlights
Vertebrates are armed with innate and adaptive immune systems to withstand invasive viruses and other microbes
The result showed that C. idella MDA5 (CiMDA5) and CiRIG-I were overexpressed in melanoma differentiation-associated protein 5 (MDA5)+ and retinoic acid-inducible gene I (RIG-I)+
We asked whether CiMDA5 and CiRIG-I played an identical role in the induction of CiIFNs after immunostimulation
Summary
Vertebrates are armed with innate and adaptive immune systems to withstand invasive viruses and other microbes. The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I, melanoma differentiation-associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), are crucial PRRs in the recognition of viral RNA in the cytosol [2] They share a DExD/H-box RNA helicase domain that hydrolyzes ATP to unwind RNA and a C-terminal autoregulatory domain (CTD or RD) that is responsible for initial RNA binding [3]. Once the CARD–CARD interaction shapes, MAVS forms functional prion-like aggregates and recruits several tumor receptor-associated factors (TRAFs) to activate IκB kinases (IKKs) and TRAF-associated NF-κB activator-binding kinase (TBK) 1 [5, 6], and thereby recruits IFN regulatory factor (IRF) 3 for its phosphorylation activation and the subsequent nucleus translocation [7] In this regard, another major transcription factor IRF7, a typical IFN-stimulated gene (ISG), is implicated in RLR signaling pathway as well [8, 9]. Similar to IRF3, phosphorylation-activated IRF7 undergoes nucleus translocation and cooperates with activated IRF3 to bind the promoter regions of IFN genes for the expression initiation following viral infection [10]
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