title: MDA5 localizes to stress granules, but this localization is not required for the induction of type I interferon.
abstract: Virus infection can initiate a type I interferon (IFN-α/β) response via activation of the cytosolic RNA sensors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Furthermore, it can activate kinases that phosphorylate eukaryotic translation initiation factor 2α (eIF2α), which leads to inhibition of (viral) protein translation and formation of stress granules (SG). Most viruses have evolved mechanisms to suppress these cellular responses. Here, we show that a mutant mengovirus expressing an inactive leader (L) protein, which we have previously shown to be unable to suppress IFN-α/β, triggered SG formation in a protein kinase R (PKR)-dependent manner. Furthermore, we show that infection of cells that are defective in SG formation yielded higher viral RNA levels, suggesting that SG formation acts as an antiviral defense mechanism. Since the induction of both IFN-α/β and SG is suppressed by mengovirus L, we set out to investigate a potential link between these pathways. We observed that MDA5, the intracellular RNA sensor that recognizes picornaviruses, localized to SG. However, activation of the MDA5 signaling pathway did not trigger and was not required for SG formation. Moreover, cells that were unable to form SG-by protein kinase R (PKR) depletion, using cells expressing a nonphosphorylatable eIF2α protein, or by drug treatment that inhibits SG formation-displayed a normal IFN-α/β response. Thus, although MDA5 localizes to SG, this localization seems to be dispensable for induction of the IFN-α/β pathway.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences & Nijmegen Institute for Infection, Inflammation and Immunology, Nijmegen, The Netherlands.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Langereis
authors.forename: Qian
authors.initials: Q
authors.lastname: Feng
authors.forename: Frank J
authors.initials: FJ
authors.lastname: van Kuppeveld
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D003594:Cytoplasmic Granules / Q000201:enzymology* / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha / Q000235:genetics* / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism; D008574:Mengovirus / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport
chemical_list: D016898:Interferon-alpha; D016899:Interferon-beta; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
references.citation: J Virol. 2001 Sep;75(17):7811-7
references.pmid: 11483724
references.citation: Mol Cell. 2009 Dec 25;36(6):932-41
references.pmid: 20064460
references.citation: Immunity. 2012 Jun 29;36(6):933-46
references.pmid: 22749352
references.citation: Mol Cell Biol. 2000 Jul;20(13):4532-42
references.pmid: 10848580
references.citation: Science. 2007 Nov 30;318(5855):1455-8
references.pmid: 18048689
references.citation: J Virol. 2010 Apr;84(7):3654-65
references.pmid: 20106928
references.citation: Nature. 1999 Jan 21;397(6716):271-4
references.pmid: 9930704
references.citation: Mol Cell. 2001 Jun;7(6):1165-76
references.pmid: 11430820
references.citation: Cell Microbiol. 2007 Dec;9(12):2921-30
references.pmid: 17991048
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14050-5
references.pmid: 17709747
references.citation: J Virol. 2007 Apr;81(8):3677-84
references.pmid: 17267501
references.citation: J Biol Chem. 1999 Feb 26;274(9):5953-62
references.pmid: 10026221
references.citation: Cell Host Microbe. 2012 Jul 19;12(1):71-85
references.pmid: 22817989
references.citation: EMBO J. 2006 Apr 19;25(8):1730-40
references.pmid: 16601681
references.citation: J Biol Chem. 2002 Oct 11;277(41):38364-72
references.pmid: 12161430
references.citation: J Exp Med. 2008 Jul 7;205(7):1601-10
references.pmid: 18591409
references.citation: J Virol. 2010 Dec;84(23):12274-84
references.pmid: 20844027
references.citation: Pharmacol Ther. 2009 Nov;124(2):219-34
references.pmid: 19615405
references.citation: EMBO J. 1995 Dec 15;14(24):6095-106
references.pmid: 8557029
references.citation: J Virol. 2011 Sep;85(18):9614-22
references.pmid: 21752908
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12067-72
references.pmid: 19574455
references.citation: Cell Microbiol. 2007 Sep;9(9):2218-29
references.pmid: 17490409
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14046-51
references.pmid: 18780793
references.citation: Immunity. 2012 Jun 29;36(6):959-73
references.pmid: 22705106
references.citation: J Virol. 2009 Jul;83(14):7273-84
references.pmid: 19420082
references.citation: Cell. 2005 Sep 9;122(5):669-82
references.pmid: 16125763
references.citation: J Immunol. 2005 Sep 1;175(5):2851-8
references.pmid: 16116171
references.citation: J Virol. 2000 Dec;74(24):11566-73
references.pmid: 11090154
references.citation: J Virol. 2011 Dec;85(23):12442-54
references.pmid: 21957303
references.citation: J Gen Virol. 2009 Jan;90(Pt 1):177-86
references.pmid: 19088287
references.citation: J Virol. 2011 Apr;85(8):3717-32
references.pmid: 21307186
references.citation: Autophagy. 2011 Jun;7(6):613-28
references.pmid: 21460631
references.citation: Nature. 2007 Dec 20;450(7173):1253-7
references.pmid: 18097414
references.citation: Cell Signal. 2006 Nov;18(11):1865-75
references.pmid: 16600570
references.citation: Cell Host Microbe. 2007 Nov 15;2(5):295-305
references.pmid: 18005751
references.citation: Mol Cell Biol. 2001 Jan;21(1):61-72
references.pmid: 11113181
references.citation: Mol Cell. 2000 Nov;6(5):1099-108
references.pmid: 11106749
references.citation: Cell. 1992 Feb 7;68(3):585-96
references.pmid: 1739968
references.citation: Cell Host Microbe. 2008 Apr 17;3(4):206-12
references.pmid: 18407064
references.citation: Mol Cell. 2009 Jan 16;33(1):87-96
references.pmid: 19150430
references.citation: Mol Biol Cell. 2007 Jul;18(7):2603-18
references.pmid: 17475769
references.citation: Mol Biol Cell. 2002 Jan;13(1):195-210
references.pmid: 11809833
references.citation: FASEB J. 2012 Apr;26(4):1629-39
references.pmid: 22202676
references.citation: Immunity. 1999 Dec;11(6):721-31
references.pmid: 10626894
references.citation: Cell Rep. 2012 Nov 29;2(5):1187-96
references.pmid: 23142662
references.citation: RNA. 2008 Mar;14(3):425-31
references.pmid: 18174314
references.citation: J Virol. 2005 Apr;79(8):5163-73
references.pmid: 15795300
references.citation: EMBO J. 2008 Apr 9;27(7):1110-21
references.pmid: 18337753
references.citation: Nat Rev Microbiol. 2010 Dec;8(12):867-78
references.pmid: 21060318
references.citation: Cell Host Microbe. 2010 May 20;7(5):354-61
references.pmid: 20478537
references.citation: Cell. 1977 May;11(1):187-200
references.pmid: 559547
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21010-5
references.pmid: 22160685
references.citation: J Virol. 2002 Oct;76(19):9664-72
references.pmid: 12208945
references.citation: PLoS Pathog. 2012;8(5):e1002708
references.pmid: 22615568
references.citation: EMBO J. 2012 Apr 4;31(7):1714-26
references.pmid: 22314235
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):637-42
references.pmid: 11805321
references.citation: Nature. 2006 May 4;441(7089):101-5
references.pmid: 16625202
references.citation: Cell. 2002 Feb 22;108(4):545-56
references.pmid: 11909525
references.citation: Science. 2006 Nov 10;314(5801):994-7
references.pmid: 17038590
references.citation: PLoS Pathog. 2011 Mar;7(3):e1001311
references.pmid: 21436888
references.citation: PLoS One. 2012;7(8):e43031
references.pmid: 22912779
references.citation: Mol Cell. 2000 May;5(5):897-904
references.pmid: 10882126
references.citation: Cell. 2011 Aug 5;146(3):448-61
references.pmid: 21782231
references.citation: EMBO J. 2001 Dec 3;20(23):6909-18
references.pmid: 11726526
references.citation: Trends Microbiol. 2012 Apr;20(4):175-83
references.pmid: 22405519
references.citation: J Cell Biol. 2000 Dec 11;151(6):1257-68
references.pmid: 11121440