Abstract
Laboratory of genetics and physiology 2 (LGP2) is a key component of RIG-I-like receptors (RLRs). However, the lack of the caspase recruitment domains (CARDs) results in its controversial functional performance as a negative or positive regulator in antiviral responses. Especially, no sufficient evidence uncovers the functional mechanisms of LGP2 in RLR signaling pathways in teleost. Here, negative regulation mechanism of LGP2 in certain situations in retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5)-mediated antiviral responses was identified in Ctenopharyngodon idella kidney cells. LGP2 overexpression inhibits synthesis and phosphorylation of interferon regulatory factor 3/7 (IRF3/7), and mRNA levels and promoter activities of IFNs and NF-κBs in resting state and early phase of grass carp reovirus (GCRV) infection. Knockdown of LGP2 obtains opposite effects. Luciferase report assay indicates that LGP2 works at the upstream of RIG-I and MDA5. LGP2 binds to RIG-I and MDA5 with diverse domain preference and which is independent of GCRV infection. Furthermore, LGP2 restrains K63-linked ubiquitination of RIG-I and MDA5 in various degrees. These differences result in disparate repressive mechanisms of LGP2 to RIG-I- and MDA5-mediated signal activations of IFN-β promoter stimulator 1 and mediator of IRF3 activation. Interestingly, LGP2 also inhibits K48-linked RIG-I and MDA5 ubiquitination to suppress proteins degradation, which guarantees the basal protein levels for subsequently rapid signal activation. All these results reveal a mechanism that LGP2 functions as a suppressor in RLR signaling pathways to maintain cellular homeostasis in resting state and early phase during GCRV infection.
Highlights
The host possesses intrinsic antiviral immune system that binds viral components and inhibits viral replication [1]
Three members have been identified in this family: retinoic acidinducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2), and all of them belong to DExD/H box RNA helicases family [5]
In contrast to previous reports of LGP2 as a positive regulator of MDA5- and RIG-I-mediated viral recognition [16, 18, 51], our present study demonstrates that grass carp LGP2 is a negative regulator in RIG-I- and MDA5-mediated antiviral signaling pathway at resting state and early phase during grass carp reovirus (GCRV) infection
Summary
The host possesses intrinsic antiviral immune system that binds viral components and inhibits viral replication [1]. Pattern recognition receptors (PRRs) directly sense the presence of pathogen components, so called pathogen-associated molecular patterns (PAMPs) [2, 3]. RIG-I and MDA5 have been well characterized: RIG-I mainly recognizes RNAs with 5’ PPP or short dsRNA (~20 bp), while RNA web can induce the activation of MDA5 [1, 7] Both RIG-I and MDA5 can sense a wide variety of RNA or DNA viruses [1, 7]. RIG-I and MDA5 activate nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) through the adaptor proteins IFN-β promoter stimulator 1 [(IPS-1), known as MAVS, VISA, or Cardif] and mediator of IRF3 activation [MITA, named as STING] [8, 9]. MITA functions downstream of RIG-I and IPS-1, which is necessary for efficient induction of IFN-Is and IFN-stimulated genes (ISGs) [8, 10]
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