| Structural highlights
Function
DHX58_HUMAN Acts as a regulator of DDX58/RIG-I and IFIH1/MDA5 mediated antiviral signaling. Cannot initiate antiviral signaling as it lacks the CARD domain required for activating MAVS/IPS1-dependent signaling events. Can have both negative and positive regulatory functions related to DDX58/RIG-I and IFIH1/MDA5 signaling and this role in regulating signaling may be complex and could probably depend on characteristics of the infecting virus or target cells, or both. Its inhibitory action on DDX58/RIG-I signaling may involve the following mechanisms: competition with DDX58/RIG-I for binding to the viral RNA, binding to DDX58/RIG-I and inhibiting its dimerization and interaction with MAVS/IPS1, competing with IKBKE in its binding to MAVS/IPS1 thereby inhibiting activation of interferon regulatory factor 3 (IRF3). Its positive regulatory role may involve unwinding or stripping nucleoproteins of viral RNA thereby facilitating their recognition by DDX58/RIG-I and IFIH1/MDA5. Involved in the innate immune response to various RNA viruses and some DNA viruses such as poxviruses, and also to the bacterial pathogen Listeria monocytogenes. Can bind both ssRNA and dsRNA, with a higher affinity for dsRNA. Shows a preference to 5'-triphosphorylated RNA, although it can recognize RNA lacking a 5'-triphosphate.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The RIG-I-like receptors (RLRs), RIG-I and MDA5, recognize single-stranded RNA with 5' triphosphates and double-stranded RNA (dsRNA) to initiate innate antiviral immune responses. LGP2, a homolog of RIG-I and MDA5 that lacks signaling capability, regulates the signaling of the RLRs. To establish the structural basis of dsRNA recognition by the RLRs, we have determined the 2.0-A resolution crystal structure of human LGP2 C-terminal domain bound to an 8-bp dsRNA. Two LGP2 C-terminal domain molecules bind to the termini of dsRNA with minimal contacts between the protein molecules. Gel filtration chromatography and analytical ultracentrifugation demonstrated that LGP2 binds blunt-ended dsRNA of different lengths, forming complexes with 2:1 stoichiometry. dsRNA with protruding termini bind LGP2 and RIG-I weakly and do not stimulate the activation of RIG-I efficiently in cells. Surprisingly, full-length LGP2 containing mutations that abolish dsRNA binding retained the ability to inhibit RIG-I signaling.
The RIG-I-like receptor LGP2 recognizes the termini of double-stranded RNA.,Li X, Ranjith-Kumar CT, Brooks MT, Dharmaiah S, Herr AB, Kao C, Li P J Biol Chem. 2009 May 15;284(20):13881-91. Epub 2009 Mar 11. PMID:19278996[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M Jr, Akira S, Yonehara S, Kato A, Fujita T. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 2005 Sep 1;175(5):2851-8. PMID:16116171
- ↑ Komuro A, Horvath CM. RNA- and virus-independent inhibition of antiviral signaling by RNA helicase LGP2. J Virol. 2006 Dec;80(24):12332-42. Epub 2006 Oct 4. PMID:17020950 doi:http://dx.doi.org/10.1128/JVI.01325-06
- ↑ Saito T, Hirai R, Loo YM, Owen D, Johnson CL, Sinha SC, Akira S, Fujita T, Gale M Jr. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):582-7. Epub 2006 Dec 26. PMID:17190814 doi:0606699104
- ↑ Murali A, Li X, Ranjith-Kumar CT, Bhardwaj K, Holzenburg A, Li P, Kao CC. Structure and function of LGP2, a DEX(D/H) helicase that regulates the innate immunity response. J Biol Chem. 2008 Jun 6;283(23):15825-33. doi: 10.1074/jbc.M800542200. Epub 2008 , Apr 14. PMID:18411269 doi:http://dx.doi.org/10.1074/jbc.M800542200
- ↑ Bamming D, Horvath CM. Regulation of signal transduction by enzymatically inactive antiviral RNA helicase proteins MDA5, RIG-I, and LGP2. J Biol Chem. 2009 Apr 10;284(15):9700-12. doi: 10.1074/jbc.M807365200. Epub 2009 , Feb 11. PMID:19211564 doi:10.1074/jbc.M807365200
- ↑ Broquet AH, Hirata Y, McAllister CS, Kagnoff MF. RIG-I/MDA5/MAVS are required to signal a protective IFN response in rotavirus-infected intestinal epithelium. J Immunol. 2011 Feb 1;186(3):1618-26. doi: 10.4049/jimmunol.1002862. Epub 2010, Dec 27. PMID:21187438 doi:http://dx.doi.org/10.4049/jimmunol.1002862
- ↑ Chopy D, Pothlichet J, Lafage M, Megret F, Fiette L, Si-Tahar M, Lafon M. Ambivalent role of the innate immune response in rabies virus pathogenesis. J Virol. 2011 Jul;85(13):6657-68. doi: 10.1128/JVI.00302-11. Epub 2011 Apr 27. PMID:21525357 doi:http://dx.doi.org/10.1128/JVI.00302-11
- ↑ Li X, Ranjith-Kumar CT, Brooks MT, Dharmaiah S, Herr AB, Kao C, Li P. The RIG-I-like receptor LGP2 recognizes the termini of double-stranded RNA. J Biol Chem. 2009 May 15;284(20):13881-91. Epub 2009 Mar 11. PMID:19278996 doi:10.1074/jbc.M900818200
- ↑ Takahasi K, Kumeta H, Tsuduki N, Narita R, Shigemoto T, Hirai R, Yoneyama M, Horiuchi M, Ogura K, Fujita T, Inagaki F. 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. 2009 Jun 26;284(26):17465-74. Epub 2009 Apr 20. PMID:19380577 doi:10.1074/jbc.M109.007179
- ↑ Pippig DA, Hellmuth JC, Cui S, Kirchhofer A, Lammens K, Lammens A, Schmidt A, Rothenfusser S, Hopfner KP. The regulatory domain of the RIG-I family ATPase LGP2 senses double-stranded RNA. Nucleic Acids Res. 2009 Apr;37(6):2014-25. Epub 2009 Feb 10. PMID:19208642 doi:10.1093/nar/gkp059
- ↑ Li X, Ranjith-Kumar CT, Brooks MT, Dharmaiah S, Herr AB, Kao C, Li P. The RIG-I-like receptor LGP2 recognizes the termini of double-stranded RNA. J Biol Chem. 2009 May 15;284(20):13881-91. Epub 2009 Mar 11. PMID:19278996 doi:10.1074/jbc.M900818200
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