WikiJournal Preprints/RIG-I

From Wikiversity
Jump to navigation Jump to search

WikiJournal Preprints logo.svg

WikiJournal Preprints
Open access • Publication charge free • Public peer review

WikiJournal User Group is a publishing group of open-access, free-to-publish, Wikipedia-integrated academic journals. <seo title=" Wikiversity Journal User Group, WikiJournal Free to publish, Open access, Open-access, Non-profit, online journal, Public peer review "/>

<meta name='citation_doi' value=>

Article information

Author: Natalie Borg[i]

, Wikidata [[:d:|]] Missing or empty |title= (help)


Abstract text goes here

RIG-I like receptors and their ligands[edit | edit source]

RIG-I (retinoic-acid inducible gene I) is the best characterized receptor within the RLR (RIG-I-like receptor family) family. Together with MDA5 (melanoma differentiation-associated 5) and LGP2 (laboratory of genetics and physiology 2), this family of receptors are involved in the cellular front line defense against viral infections. As soluble pattern recognition receptors (PRRs) that are located in the cytoplasm of the cell, the RLRs are sentinels for intracellular viral RNA that is a product of viral infection. The RIG-I receptor prefers to bind single- or double-stranded RNA carrying an uncapped 5’ triphosphate and additional motifs such as poly-uridine rich RNA motifs (Saito nature 2008 523). RIG-I triggers an immune response to RNA viruses from various families including the Paramyxoviruses (e.g. measles), Rhabdoviruses (e.g. Vesicular Stomatitis virus) and Orthomyxoviruses (e.g. influenza A) (Baum et al, 2010; Gitlin et al, 2006; Hornung et al, 2006; Schlee et al, 2009; Wang & Ryu, 2010). The viral RNA preferred by MDA5 is poorly characterized, but MDA5 is essential in the detection of double stranded RNA from Picornaviruses (e.g. encephalomyelitis virus) (Kato et al, 2006). Although RIG-I and MDA5 respond to distinct viruses, there are cases where their specificity overlaps. For example, both RIG-I and MDA5 respond to dengue virus and West Nile virus, which are both Flaviviruses (Fredericksen et al, 2008; Loo et al, 2008; Nasirudeen et al, 2011), and their role, at least in West Nile virus infection is complementary (Errett et al, 2013). The ligands of LGP2 are also poorly characterized, but LGP2 prefers double-stranded RNA over single-stranded RNA (Murali et al, 2008).

Example image.png

 Image caption text goes here

name of image creator, CC-BY 3.0

Structural features of the RLR receptors[edit | edit source]

The RLR receptors share a common domain architecture. All three receptors are members of the DExD/H box helicase family that is characterized by a core catalytic helicase domain made up of two RecA-like domains. The catalytic core contains at least 9 highly conserved sequence motifs that coordinate ATP and RNA binding and the hydrolysis of ATP to unwind RNA. A C-terminal domain (CTD) follows the helicase core and this domain also binds viral RNA. Distinct RNA-binding loops within the CTD of three RLRs confer dictate the type of RNA they can bind (Takahasi et al, 2009). In addition to the helicase core and CTD, RIG-I and MDA5 have two N-terminal CARD (caspase active recruitment domains) domains that are essential to the initiation of downstream signaling. LGP2 is dissimilar to RIG-I and MDA5 as it lacks the CARD signaling domains and this has implications for its function.

RIG-I antiviral signaling[edit | edit source]

In uninfected cells that are absent of viral RNA RIG-I exists in an inactive conformation in which the CARD domains are masked due to their interaction with the CTD (Luo et al, 2011). Upon binding RNA RIG-I changes into a conformation in which the CARD domains are exposed and ‘available’ for signaling. As an additional safeguard, these exposed CARDs can undergo modifications (e.g. ubiquitination, phosphorylation) that either positively or negatively regulate RIG-I signaling. In the activated state the exposed RIG-I CARD domains interact with the CARD domains of MAVS (mitochondrial anti-viral signaling protein, also known as IPS-1, VISA or Cardif) which sits on the outer surface of the mitochondria. This binding event is essential to signaling as it causes MAVS to form large functional aggregates which activate the transcription factors interferon regulatory factor (IRF)-3, IRF7 and NF-kb (nuclear factor kappa B) which leads to the production of proinflammatory cytokine and type I and type III interferons (IFN). Although secreted IFNs are in themselves antiviral agents, they prompt the production of more antiviral agents. The type I IFNs (IFNa and IFNb) accomplish this by binding cell surface type I IFN receptors to activate JAK-STAT (Janus kinase/signal transducers and activators of transcription) signaling. Overall this causes the death of infected cells, the protection of surrounding cells and the activation of the antigen-specific antiviral immune response. Collectively this coordinated antiviral immune response controls the viral infection.

Unlike RIG-I MDA5 is uninhibited in the absence of RNA and exists in an extended conformation (Berke & Modis, 2012) in which the CARDs are unhindered. However, as per RIG-I, the CARDs of MDA5 are modified as a means of regulating signaling via MAVS. Given LGP2 lacks CARD signaling domains it is unable to bind MAVS to initiate signaling. Instead, LGP2 is both a positive and negative regulator of RIG-I and MDA5, and consequently signaling (Bruns et al, 2014; Childs et al, 2013; Komuro & Horvath, 2006; Parisien et al, 2018; Saito et al, 2007; Satoh et al, 2010; Uchikawa et al, 2016)

Regulation of RLR signaling[edit | edit source]

As prolonged IFN production is linked to human disease, RLR signaling must be tightly regulated. One of various ways that this is achieved is by modifying or tagging host RLR signaling proteins with ubiquitin, a small 8 kDa protein. This process is called ubiquitination and is carried out by enzymes known as E3 ligases. These tags can also be removed, which adds an additional regulatory layer to RLR signaling. These modifications, and their removal, are prevalent in RLR signaling and even regulate the RIG-I receptor itself.  Most famously the ubiquitination of the exposed RIG-I CARDs by the E3 ligase TRIM25 is essential to the induction of the RLR-mediated antiviral immune response (Gack et al, 2007). This modification is so pertinent to the success of RLR signaling that it is targeted by the influenza A virus.

Viral hijacking of RLR signaling[edit | edit source]

Viruses have evolved ways to subvert RLR signaling to enhance their survival. For example, influenza A uses its NS1 (nonstructural protein 1) protein to block TRIM25 from ubiquitinating RIG-I and this in turn inhibits IFN production (Gack et al, 2009). This outcome is also achieved by the hepatitis C NS3/4A protein by removing a part of MAVS (Li 2005 PNAS 17717) and the foot-and-mouth disease Leader protease (Lpro) which cleaves LGP2 (Rodriguez Pulido et al, 2018). Another prominent example is that of the Paramyxovirus V proteins, which directly bind various RLR signaling proteins including MDA5, LGP2, and STAT (Andrejeva et al, 2004; Childs et al, 2007; Rodriguez & Horvath, 2014)   

Additional information[edit | edit source]

Acknowledgements[edit | edit source]

Any people, organisations, or funding sources that you would like to thank.

Competing interests[edit | edit source]

Any conflicts of interest that you would like to declare. Otherwise, a statement that the authors have no competing interest.

Ethics statement[edit | edit source]

An ethics statement, if appropriate, on any animal or human research performed should be included here or in the methods section.

References[edit | edit source]

Andrejeva, J., Childs, K. S., Young, D. F., Carlos, T. S., Stock, N., Goodbourn, S. & Randall, R. E. (2004) The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci U S A, 101(49), 17264-9.

Baum, A., Sachidanandam, R. & Garcia-Sastre, A. (2010) Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing. Proc Natl Acad Sci U S A, 107(37), 16303-8.

Berke, I. C. & Modis, Y. (2012) MDA5 cooperatively forms dimers and ATP-sensitive filaments upon binding double-stranded RNA. EMBO J, 31(7), 1714-26.

Bruns, A. M., Leser, G. P., Lamb, R. A. & Horvath, C. M. (2014) The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament assembly. Mol Cell, 55(5), 771-81.

Childs, K., Stock, N., Ross, C., Andrejeva, J., Hilton, L., Skinner, M., Randall, R. & Goodbourn, S. (2007) mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology, 359(1), 190-200.

Childs, K. S., Randall, R. E. & Goodbourn, S. (2013) LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA. PLoS One, 8(5), e64202.

Errett, J. S., Suthar, M. S., McMillan, A., Diamond, M. S. & Gale, M., Jr. (2013) The essential, nonredundant roles of RIG-I and MDA5 in detecting and controlling West Nile virus infection. J Virol, 87(21), 11416-25.

Fredericksen, B. L., Keller, B. C., Fornek, J., Katze, M. G. & Gale, M., Jr. (2008) Establishment and maintenance of the innate antiviral response to West Nile Virus involves both RIG-I and MDA5 signaling through IPS-1. J Virol, 82(2), 609-16.

Gack, M. U., Albrecht, R. A., Urano, T., Inn, K. S., Huang, I. C., Carnero, E., Farzan, M., Inoue, S., Jung, J. U. & Garcia-Sastre, A. (2009) Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell host & microbe, 5(5), 439-49.

Gack, M. U., Shin, Y. C., Joo, C. H., Urano, T., Liang, C., Sun, L., Takeuchi, O., Akira, S., Chen, Z., Inoue, S. & Jung, J. U. (2007) TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature, 446(7138), 916-920.

Gitlin, L., Barchet, W., Gilfillan, S., Cella, M., Beutler, B., Flavell, R. A., Diamond, M. S. & Colonna, M. (2006) Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci U S A, 103(22), 8459-64.

Hornung, V., Ellegast, J., Kim, S., Brzozka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K. K., Schlee, M., Endres, S. & Hartmann, G. (2006) 5'-Triphosphate RNA is the ligand for RIG-I. Science, 314(5801), 994-7.

Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K. J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C. S., Reis e Sousa, C., Matsuura, Y., Fujita, T. & Akira, S. (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature, 441(7089), 101-5.

Komuro, A. & Horvath, C. M. (2006) RNA- and virus-independent inhibition of antiviral signaling by RNA helicase LGP2. J Virol, 80(24), 12332-42.

Loo, Y. M., Fornek, J., Crochet, N., Bajwa, G., Perwitasari, O., Martinez-Sobrido, L., Akira, S., Gill, M. A., Garcia-Sastre, A., Katze, M. G. & Gale, M., Jr. (2008) Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol, 82(1), 335-45.

Luo, D., Ding, S. C., Vela, A., Kohlway, A., Lindenbach, B. D. & Pyle, A. M. (2011) Structural insights into RNA recognition by RIG-I. Cell, 147(2), 409-22.

Murali, A., Li, X., Ranjith-Kumar, C. T., Bhardwaj, K., Holzenburg, A., Li, P. & Kao, C. C. (2008) Structure and function of LGP2, a DEX(D/H) helicase that regulates the innate immunity response. J Biol Chem, 283(23), 15825-33.

Nasirudeen, A. M., Wong, H. H., Thien, P., Xu, S., Lam, K. P. & Liu, D. X. (2011) RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection. PLoS Negl Trop Dis, 5(1), e926.

Parisien, J. P., Lenoir, J. J., Mandhana, R., Rodriguez, K. R., Qian, K., Bruns, A. M. & Horvath, C. M. (2018) RNA sensor LGP2 inhibits TRAF ubiquitin ligase to negatively regulate innate immune signaling. EMBO Rep, 19(6).

Rodriguez, K. R. & Horvath, C. M. (2014) Paramyxovirus V protein interaction with the antiviral sensor LGP2 disrupts MDA5 signaling enhancement but is not relevant to LGP2-mediated RLR signaling inhibition. J Virol, 88(14), 8180-8.

Rodriguez Pulido, M., Sanchez-Aparicio, M. T., Martinez-Salas, E., Garcia-Sastre, A., Sobrino, F. & Saiz, M. (2018) Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus. PLoS Pathog, 14(6), e1007135.

Saito, T., Hirai, R., Loo, Y. M., Owen, D., Johnson, C. L., Sinha, S. C., Akira, S., Fujita, T. & Gale, M., Jr. (2007) Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci U S A, 104(2), 582-7.

Satoh, T., Kato, H., Kumagai, Y., Yoneyama, M., Sato, S., Matsushita, K., Tsujimura, T., Fujita, T., Akira, S. & Takeuchi, O. (2010) LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc Natl Acad Sci U S A, 107(4), 1512-7.

Schlee, M., Roth, A., Hornung, V., Hagmann, C. A., Wimmenauer, V., Barchet, W., Coch, C., Janke, M., Mihailovic, A., Wardle, G., Juranek, S., Kato, H., Kawai, T., Poeck, H., Fitzgerald, K. A., Takeuchi, O., Akira, S., Tuschl, T., Latz, E., Ludwig, J. & Hartmann, G. (2009) Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity, 31(1), 25-34.

Takahasi, K., Kumeta, H., Tsuduki, N., Narita, R., Shigemoto, T., Hirai, R., Yoneyama, M., Horiuchi, M., Ogura, K., Fujita, T. & Inagaki, F. (2009) Solution structures of cytosolic RNA sensor MDA5 and LGP2 C-terminal domains: identification of the RNA recognition loop in RIG-I-like receptors. J Biol Chem, 284(26), 17465-74.

Uchikawa, E., Lethier, M., Malet, H., Brunel, J., Gerlier, D. & Cusack, S. (2016) Structural Analysis of dsRNA Binding to Anti-viral Pattern Recognition Receptors LGP2 and MDA5. Mol Cell, 62(4), 586-602.

Wang, H. & Ryu, W. S. (2010) Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: implications for immune evasion. PLoS pathogens, 6(7), e1000986.