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A variety of pathogens, including viruses, can trigger an innate cellular immune response that is essential to limit the early spread of pathogens. After the virus infects the body, the development of effective antiviral natural immunity requires the activation of a robust, specific immune system. This process relies on the ability of the host cell to first sense the virus and then alert neighboring cells or some immune cells about virus infections to proceed. The transmission of this signal in cells requires a class of pattern-recognition receptors (PRRs) to specifically recognize the pathogen associated molecular pattern (PAMP) of viral expression. This type of pattern-recognition receptor mainly includes Toll like receptors (TLRs), RIG-1 like receptors (RLRs), NOD-like receptors (NOD-like receptors, NLRs), Hin-200 family proteins and some DNA receptors. The RLRs in PRRs are a class of RNA helicases in the cytoplasm that recognize non-self viral RNA by binding their pathogen associated molecular pattern (PAMP) to their RNA ligands. In infected cells, this interaction can lead to the production of type I interferons and the production of inflammatory factors by triggering the activation of RLRs and downstream signaling molecules, which make an antiviral immune response.
Members of RLRs include retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of Genetics and Physiology 2 (LGP2). They all contain a special DEX/DH box which is RNase helix domain, so RLRs can bind with RNA. In addition, they all have ATPase function, and ATP hydrolysis will change the RNA conformation, and then the conformational changes of RNA will activate the transduction of downstream signals. In addition to LGP2, RIG-I and MDA5 all have two N-terminal CARD domains (caspase activation and recruitment domains) which promote their interactions with other molecules comprising this domain. The interaction of these domains promotes the binding of RIG-I/MDA5 to an important linker molecule MAVS (mitochondrial antiviral signaling protein, also known as IPS-1/VISA/Cardif), which also contains the CARD domain, and leads to activation of factor IRF-3, IRF-7 (interferon regulatory factors) and importing NF-κB into nuclear (nuclear factor κB). This process ultimately results in the activation of various antiviral genes such as interferon, interferon-stimulated genes, and pro-inflammatory factors, thereby inhibiting the replication and spread of the virus. The C-terminal domain of RIG-I and LGP2 contains a repressor domain (RD domain), which allows RIG-I and LGP2 to be in a non-activated state when the cells are not stimulated by the viral RNA. Depending on previous studies, the researchers found that RIG-I and MAD5 can recognize many different kinds of virus, and can be activated. For example, RIG-I can recognize viruses mainly including Paramyxoviridae, such as newcastle disease virus; Corynevirus, such as rabies virus; Orthomyxoviridae, such as influenza virus; Flaviviridae, such as hepatitis virus. In contrast, MDA5 primarily recognizes picornavirus families such as EMCV; and coronaviruses such as murine hepatitis virus. In addition, both RIG-I and MDA5 recognize dengue virus, new Nile virus, and reovirus.
In this process, the essential question is how the RLRs recognize the RNA of the virus. Studies have shown that RNA containing a 5'-end triphosphate (5'ppp) tail is a prerequisite for recognition by RIG-I, and complete removal of 5'ppp completely prevents activation of the RIG-I signaling pathway. This structure allows RIG-I to distinguish between host cell RNA and viral RNA because the host cell RNA has a cap structure at the 5' end and tRNA and rRNA lack a 5'ppp structure. For MDA5 and LGP2, the character of recognition is not certain.
After the RLR recognizes the viral RNA, it activates MAVS, and then transduces the signal to the downstream TRAF3, TBK1 kinase and IKK-I complex, and then phosphorylates and activates IRF3/7, and the activated IRF3/7 is transferred to the nucleus. Finally, the production of type I interferon is induced. Activated MAVS can also pass TRAF2/6 ( tumornecrosis factor (TNF) R-associated factor 2/6) or FADD (Fas-associated death domain), RIP1 (receptor interacting protein-1), and TRADD (TANK-binding kinase-1), and Caspase 8 /10 pathways transduce signals to IKK complexes (including IKKα, IKKβ, IKKγ), and finally lead to phosphorylation of NF-κB and IκBα complexes. Phosphorylated IκBα sheds and degrades from NF-κB, and activated NF-κB enters the nucleus to promote the production of pro-inflammatory factors and inflammatory chemokines. In addition, another linker molecule, STING (stimulator of interferon genes), can also interact with RIG-I and MAVS to activate IRF/IFN. Numerous experiments have demonstrated that DNA plays an important role in stimulating IFN production. However, the role of STING in RNA virus-stimulated intracellular RLR signaling is unclear. Interestingly, studies have shown that RIG-1 can be regulated by ubiquitin-protein ligase (E3). For example, TRIM25(tripartite motif containing 25) can be combined with RIG-I as a ubiquitin ligase to ubiquitinate K17 lysine residues in the CARD domain, and finally the ubiquitination leads to the activation of RIG-I and MAVS. In addition, E2 ubiquitin-conjugating enzyme 5 is involved in the activation of RIG-I signaling pathway, which may be involved in K63 ubiquitination of IKKγ, which is downstream of MAVS, and promotes the activation of TBK1 and IRF/NF-kB by IKKγ. Additionally, the RIG-I pathway can also be negatively regulated by ubiquitination. The ubiquitin ligase E3, RNF125, binds the K48 ubiquitin chain to RIG-I and MDA5, promoting their degradation by the proteasome.
The RLG-I like receptor signaling pathway plays an important role in preventing the body from being infected by viruses. For this immune defense, the virus has some strategies to interfere with this process. After a virus infects cells, it often destroys the transduction of the RLR signaling pathway to escape the cellular immune response. A variety of viral proteins have been shown that RLRs can be prevented from recognizing viral RNA, targeting and binding to signal molecules in the RLR signaling pathway, and regulating or preventing signal transduction in the RLR pathway. More and more studies have reported how the virus can evade the innate immune response by regulating the RLR signaling pathway, which provides a good direction for future research on vaccines or immunoadjuvants, and can better inhibit pathogen infection and control of viral replication, providing a theoretical basis for the development of antiviral clinical trial drugs and strategies.
Figure1. RIG-I like receptor signaling pathway.
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