title: Interferon-inducible transmembrane protein 3 (IFITM3) restricts reovirus cell entry.
abstract: Reoviruses are double-stranded RNA viruses that infect the mammalian respiratory and gastrointestinal tract. Reovirus infection elicits production of type I interferons (IFNs), which trigger antiviral pathways through the induction of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, the functions of many of these genes are unknown. The interferon-inducible transmembrane (IFITM) proteins are one class of ISGs that restrict the cell entry of some enveloped viruses, including influenza A virus. One family member, IFITM3, localizes to late endosomes, where reoviruses undergo proteolytic disassembly; therefore, we sought to determine whether IFITM3 also restricts reovirus entry. IFITM3-expressing cell lines were less susceptible to infection by reovirus, as they exhibited significantly lower percentages of infected cells in comparison to control cells. Reovirus replication was also significantly reduced in IFITM3-expressing cells. Additionally, cells expressing an shRNA targeting IFITM3 exhibited a smaller decrease in infection after IFN treatment than the control cells, indicating that endogenous IFITM3 restricts reovirus infection. However, IFITM3 did not restrict entry of reovirus infectious subvirion particles (ISVPs), which do not require endosomal proteolysis, indicating that restriction occurs in the endocytic pathway. Proteolysis of outer capsid protein μ1 was delayed in IFITM3-expressing cells in comparison to control cells, suggesting that IFITM3 modulates the function of late endosomal compartments either by reducing the activity of endosomal proteases or delaying the proteolytic processing of virions. These data provide the first evidence that IFITM3 restricts infection by a nonenveloped virus and suggest that IFITM3 targets an increasing number of viruses through a shared requirement for endosomes during cell entry.
authors: Department of Biology, Colgate University, Hamilton, New York 13346, USA.
authors: Amanda A
authors: AA
authors: Anafu
authors: Christopher H
authors: CH
authors: Bowen
authors: Christopher R
authors: CR
authors: Chin
authors: Abraham L
authors: AL
authors: Brass
authors: Geoffrey H
authors: GH
authors: Holm
mesh_terms: D002213:Capsid / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000821:virology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology; D007700:Kinetics; D012089:Mammalian orthoreovirus 3 / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D030102:Orthoreovirus, Mammalian / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000502:physiology*; D014771:Virion / Q000502:physiology; D019065:Virus Assembly; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: C080082:IFITM3 protein, human; D016898:Interferon-alpha; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins
keywords: Endosomes; Innate Immunity; Interferon; Interferon-stimulated Gene; Reovirus; Virus Entry
references: Biochem Biophys Res Commun. 1978 Apr 14;81(3):947-54
references: 566549
references: Annu Rev Cell Dev Biol. 2007;23:23-43
references: 17456018
references: J Virol. 2002 Feb;76(4):1632-41
references: 11799158
references: Virology. 2007 May 10;361(2):412-25
references: 17208266
references: Nat Chem Biol. 2010 Aug;6(8):610-4
references: 20601941
references: Proc Natl Acad Sci U S A. 1983 Jul;80(13):4134-8
references: 6306663
references: Cell Host Microbe. 2007 Apr 19;1(2):147-57
references: 18005692
references: J Virol. 2003 Dec;77(24):13361-75
references: 14645591
references: J Biol Chem. 2002 Jul 5;277(27):24609-17
references: 11986312
references: J Gen Virol. 2007 Apr;88(Pt 4):1319-1323
references: 17374778
references: PLoS Pathog. 2011 Jan 06;7(1):e1001258
references: 21253575
references: J Virol. 1988 Dec;62(12):4594-604
references: 2460637
references: Innate Immun. 2012 Dec;18(6):834-45
references: 22467717
references: J Virol. 1998 Feb;72(2):1314-23
references: 9445032
references: Virology. 1969 Dec;39(4):791-810
references: 4311639
references: Biochem Biophys Res Commun. 1994 Dec 15;205(2):1318-24
references: 7802664
references: J Virol. 2001 Apr;75(8):3896-902
references: 11264378
references: Nature. 2012 Mar 25;484(7395):519-23
references: 22446628
references: J Virol. 2011 Mar;85(5):2126-37
references: 21177806
references: Cell Host Microbe. 2011 Sep 15;10(3):185-96
references: 21925107
references: J Virol. 2000 Feb;74(4):1919-30
references: 10644365
references: J Virol. 2002 Oct;76(19):9920-33
references: 12208969
references: Clin Microbiol Rev. 2009 Apr;22(2):240-73, Table of Contents
references: 19366914
references: Infect Immun. 1973 May;7(5):711-7
references: 4357988
references: Virology. 1970 Mar;40(3):478-85
references: 5437782
references: J Virol. 2012 Mar;86(6):2900-10
references: 22258243
references: Virology. 2010 Mar 15;398(2):194-200
references: 20042210
references: J Immunol. 1993 Feb 1;150(3):736-47
references: 8423337
references: J Immunol Methods. 2006 Jul 31;314(1-2):30-7
references: 16822520
references: J Immunol. 1993 Dec 1;151(11):6470-81
references: 8245480
references: J Virol. 1993 Apr;67(4):2055-63
references: 8383227
references: J Virol. 1988 Jan;62(1):246-56
references: 3275434
references: J Cell Biol. 2002 Feb 4;156(3):511-8
references: 11827983
references: PLoS Pathog. 2011 Oct;7(10):e1002337
references: 22046135
references: BMC Dev Biol. 2003 Mar 19;3:1
references: 12659663
references: J Virol. 2011 Mar;85(6):2492-503
references: 21191022
references: J Virol. 2010 Aug;84(16):8332-41
references: 20534863
references: J Virol. 1991 Sep;65(9):5102-4
references: 1870214
references: J Virol. 2012 Dec;86(23):12665-75
references: 22973022
references: J Interferon Cytokine Res. 2011 Jan;31(1):1-4
references: 21226605
references: J Biol Chem. 2012 Jun 1;287(23):19631-41
references: 22511783
references: J Virol. 2012 Aug;86(16):8346-58
references: 22674975
references: J Mol Biol. 2005 Jan 21;345(3):461-74
references: 15581891
references: Cell. 1993 Nov 5;75(3):477-86
references: 8221887
references: Eur J Biochem. 1991 Jul 15;199(2):417-23
references: 1906403
references: Cell. 2001 Feb 9;104(3):441-51
references: 11239401
references: J Biol Chem. 2007 Jul 27;282(30):21953-61
references: 17540767
references: J Virol. 2006 Mar;80(6):2760-70
references: 16501085
references: Nat Struct Mol Biol. 2008 Jul;15(7):690-8
references: 18596815
references: Cell. 1984 Oct;38(3):745-55
references: 6548414
references: J Virol. 2008 Apr;82(7):3181-91
references: 18216114
references: Genes Immun. 2006 Mar;7(2):113-21
references: 16395393
references: Cell. 1977 May;11(1):187-200
references: 559547
references: J Virol. 1987 Aug;61(8):2351-61
references: 2885424
references: PLoS Pathog. 2013 Jan;9(1):e1003124
references: 23358889
references: Biochemistry. 1986 Apr 22;25(8):2231-7
references: 3754765
references: Curr Biol. 2001 Oct 30;11(21):1680-5
references: 11696325
references: Cell. 2009 Dec 24;139(7):1243-54
references: 20064371
references: J Virol. 2010 Dec;84(24):12646-57
references: 20943977
references: J Virol. 2010 Dec;84(24):12723-32
references: 20943982
references: J Virol. 2012 Apr;86(7):3466-73
references: 22278245
references: J Virol. 2012 Apr;86(7):4009-13
references: 22278225
references: J Virol. 1992 Nov;66(11):6408-18
references: 1328674
references: Virology. 2003 Sep 15;314(1):92-100
references: 14517063
references: J Biol Chem. 1982 Dec 25;257(24):14593-6
references: 6184367
references: J Virol. 2004 Aug;78(16):8732-45
references: 15280481
references: PLoS Pathog. 2012 Sep;8(9):e1002909
references: 22969429