Activation of IFN-&#946; expression by a viral mRNA through RNase L and MDA5.
IFNs play a critical role in innate immunity against viral infections. Melanoma differentiation-associated protein 5 (MDA5), an RNA helicase, is a key component in activating the expression of type I IFNs in response to certain types of viral infection. MDA5 senses noncellular RNA and triggers the signaling cascade that leads to IFN production. Synthetic double-stranded RNAs are known activators of MDA5. Natural single-stranded RNAs have not been reported to activate MDA5, however. We have serendipitously identified a viral mRNA from parainfluenza virus 5 (PIV5) that activates IFN expression through MDA5. We provide evidence that the signaling pathway includes the antiviral enzyme RNase L. The L mRNA of PIV5 activated expression of IFN-β. We have mapped the RNA to a region of 430 nucleotides within the L mRNA of PIV5. Our results indicate that a viral mRNA, with 5'-cap and 3'-poly (A), can activate IFN expression through an RNase L-MDA5 pathway.
Department of Infectious Diseases, University of Georgia, Athens, GA 30602, USA.
Priya
P
Luthra
Dengyun
D
Sun
Robert H
RH
Silverman
Biao
B
He
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004722:Endoribonucleases / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics*; D012333:RNA, Messenger / Q000502:physiology*; D034741:RNA, Small Interfering; D012367:RNA, Viral / Q000502:physiology*; D015398:Signal Transduction
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012367:RNA, Viral; D016899:Interferon-beta; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
J Virol. 1975 Jun;15(6):1348-56
167189
J Gen Virol. 2008 Jan;89(Pt 1):1-47
18089727
J Exp Med. 2008 Jul 7;205(7):1601-10
18591409
J Virol. 2008 Jan;82(1):105-14
17959676
Cell. 2010 Feb 5;140(3):397-408
20144762
FEBS Lett. 1998 Dec 11;441(1):106-10
9877175
J Virol. 2009 Apr;83(8):3734-42
19193793
Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17264-9
15563593
Cell. 2006 Feb 24;124(4):783-801
16497588
J Virol. 2006 May;80(10):5059-64
16641297
J Virol. 2008 Jan;82(1):335-45
17942531
J Gen Virol. 2004 Oct;85(Pt 10):3007-3016
15448364
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8459-64
16714379
Gene. 1991 Dec 15;108(2):193-9
1660837
J Virol. 2004 May;78(10):5068-78
15113888
Cell. 2005 Sep 9;122(5):669-82
16125763
J Virol. 1999 Jan;73(1):251-9
9847328
J Virol. 2007 Dec;81(23):12720-9
17804500
Science. 2006 Nov 10;314(5801):997-1001
17038589
Nat Immunol. 2004 Jul;5(7):730-7
15208624
Virology. 2002 Nov 10;303(1):15-32
12482655
Virology. 1995 Apr 1;208(1):121-31
11831692
EMBO J. 1998 Nov 16;17(22):6660-9
9822609
Nature. 2006 May 4;441(7089):101-5
16625202
Virology. 2002 Nov 10;303(1):33-46
12482656
J Virol. 2009 Oct;83(20):10761-9
19656871
Virology. 2007 Nov 25;368(2):262-72
17692882
J Virol. 2005 Mar;79(5):2689-99
15708988
Nat Immunol. 2006 Feb;7(2):131-7
16424890
Nature. 2007 Aug 16;448(7155):816-9
17653195
J Virol. 2008 Nov;82(21):10887-95
18715928
J Immunol. 2008 Apr 1;180(7):4910-8
18354215