The chase for the RIG-I ligand--recent advances.
Multicellular organisms evolved efficient host-defense mechanisms to sense viruses and to block their replication and spread. Invertebrates and plants mainly rely on RNA interference (RNAi) for antiviral defense. In mammals, the initiation of antiviral defense mechanisms is largely based on the detection of viral nucleic acids by innate receptors: retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs) and Toll-like receptors (TLRs). RLHs play a pivotal role in sensing viral RNA and DNA in the cytoplasm of cells. RLHs, like Dicer of the RNAi pathway, belong to the phylogenetically conserved DExD/H-box family of helicases. Unlike TLRs, RLHs are functional in all somatic cells. Activation of RIG-I triggers antiviral responses including type I interferon (IFN), inflammasome activation and proapoptotic signaling. Here, we provide a comprehensive overview of the current literature on the ligand structures detected by RIG-I, and conclude with the molecular definition of the RIG-I ligand: short double-stranded blunt-end 5'-triphosphate RNA. The recent information on the RIG-I ligand now allows the design of short double-stranded RNA (dsRNA) oligonucleotides that are ideally suited alone or in combination with small-interfering RNA (siRNA) for the treatment of viral infection and cancer.
Schlee
Martin
M
Institute of Clinical Chemistry and Pharmacology, University Hospital Bonn, Bonn, Germany.
Hartmann
Gunther
G
D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics / Q000276:immunology; D006801:Humans; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic; D014780:Viruses / Q000235:genetics / Q000276:immunology
D004279:DNA, Viral; D012367:RNA, Viral; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8459-64
16714379
Science. 2007 Nov 30;318(5855):1455-8
18048689
J Virol. 2009 Apr;83(8):3734-42
19193793
Biochem J. 1967 Jun;103(3):62P
4292833
PLoS One. 2008 Apr 30;3(4):e2032
18446221
Nature. 2007 Aug 16;448(7155):816-9
17653195
J Biol Chem. 2007 Jun 15;282(24):17649-57
17452327
J Virol. 2007 Nov;81(22):12227-37
17804509
J Virol. 2008 Jan;82(1):335-45
17942531
Proc Natl Acad Sci U S A. 1987 Nov;84(22):8140-4
2446318
Nucleic Acids Res. 2008 Feb;36(3):e18
18208841
Proc Natl Acad Sci U S A. 2007 May 22;104(21):9035-40
17517627
Cell. 1976 Aug;8(4):547-55
182384
Cell. 1992 Jun 12;69(6):1011-20
1318785
Immunity. 2006 Jan;24(1):93-103
16413926
J Mol Biol. 2004 Jul 2;340(2):319-31
15201055
Immunity. 2005 Jul;23(1):19-28
16039576
J Exp Med. 2008 Jul 7;205(7):1601-10
18591409
Immunity. 2009 Jul 17;31(1):25-34
19576794
Nat Biotechnol. 2006 May;24(5):559-65
16648842
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12067-72
19574455
RNA. 2000 Apr;6(4):563-70
10786847
Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):582-7
17190814
J Gen Virol. 1978 Jan;38(1):35-50
202671
Oncogene. 2008 Jul 10;27(30):4150-60
18362887
J Immunol. 2005 Sep 1;175(5):2851-8
16116171
Cell. 2010 Feb 5;140(3):397-408
20144762
Nature. 2008 Jul 24;454(7203):523-7
18548002
Nat Immunol. 2010 Jan;11(1):63-9
19915568
Curr Top Microbiol Immunol. 2007;316:207-30
17969450
Nat Rev Immunol. 2007 Oct;7(10):753-66
17893693
Cell. 1981 Oct;26(2 Pt 2):145-54
7037195
PLoS Pathog. 2009 Jun;5(6):e1000473
19521506
PLoS One. 2007 Mar 14;2(3):e279
17356690
Mol Cell. 2008 Feb 1;29(2):169-79
18243112
Mol Cell. 2008 Feb 29;29(4):428-40
18242112
J Clin Invest. 2009 Aug;119(8):2399-411
19620789
Nat Immunol. 2006 Jan;7(1):40-8
16286919
Science. 2006 Nov 10;314(5801):997-1001
17038589
Nature. 2009 Nov 5;462(7269):99-103
19890330
J Virol. 1989 Jan;63(1):122-8
2908922
Nat Immunol. 2004 Jul;5(7):730-7
15208624
Immunity. 2006 May;24(5):633-42
16713980
Nat Biotechnol. 2004 Mar;22(3):321-5
14990954
Nat Immunol. 2009 Oct;10(10):1065-72
19609254
J Virol. 2005 Mar;79(5):2689-99
15708988
Nat Med. 2008 Nov;14(11):1256-63
18978796
Nature. 2006 May 4;441(7089):101-5
16625202
Science. 2006 Nov 10;314(5801):994-7
17038590
J Virol. 2009 Feb;83(3):1299-311
19036819
Curr Opin Immunol. 2008 Aug;20(4):389-95
18652893
Cell. 2009 Aug 7;138(3):576-91
19631370
J Virol. 2006 May;80(10):5059-64
16641297