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Cell Rep. 2013 Dec 26;5(6):1737-48. doi: 10.1016/j.celrep.2013.11.028. Epub 2013 Dec 12.

Genome-wide RNAi screen identifies SEC61A and VCP as conserved regulators of Sindbis virus entry.

Cell reports

Debasis Panda, Patrick P Rose, Sheri L Hanna, Beth Gold, Kaycie C Hopkins, Randolph B Lyde, Michael S Marks, Sara Cherry

Affiliations

  1. Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  3. Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].

PMID: 24332855 PMCID: PMC3920290 DOI: 10.1016/j.celrep.2013.11.028

Abstract

Alphaviruses are a large class of insect-borne human pathogens and little is known about the host-factor requirements for infection. To identify such factors, we performed a genome-wide RNAi screen using model Drosophila cells and validated 94 genes that impacted infection of Sindbis virus (SINV), the prototypical alphavirus. We identified a conserved role for SEC61A and valosin-containing protein (VCP) in facilitating SINV entry in insects and mammals. SEC61A and VCP selectively regulate trafficking of the entry receptor NRAMP2, and loss or pharmacological inhibition of these proteins leads to altered NRAMP2 trafficking to lysosomal compartments and proteolytic digestion within lysosomes. NRAMP2 is the major iron transporter in cells, and loss of NRAMP2 attenuates intracellular iron transport. Thus, this study reveals genes and pathways involved in both infection and iron homeostasis that may serve as targets for antiviral therapeutics or for iron-imbalance disorders.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

References

  1. Wiley Interdiscip Rev RNA. 2012 Mar-Apr;3(2):145-58 - PubMed
  2. Dev Dyn. 2010 Mar;239(3):784-97 - PubMed
  3. Cell. 2000 Apr 28;101(3):249-58 - PubMed
  4. Nat Cell Biol. 2011 Aug 07;13(9):1116-23 - PubMed
  5. J Cell Biol. 2012 Apr 16;197(2):219-30 - PubMed
  6. Immunity. 2012 Apr 20;36(4):658-67 - PubMed
  7. Virology. 2009 Mar 1;385(1):74-84 - PubMed
  8. Can J Physiol Pharmacol. 2006 Jan;84(1):5-14 - PubMed
  9. Biochemistry. 2006 Feb 21;45(7):2294-301 - PubMed
  10. Expert Rev Mol Med. 2008 Nov 11;10:e33 - PubMed
  11. J Virol. 2005 Dec;79(24):15043-53 - PubMed
  12. Microbiol Rev. 1994 Sep;58(3):491-562 - PubMed
  13. Curr Opin Cell Biol. 1999 Oct;11(5):540-8 - PubMed
  14. Curr Opin Microbiol. 2008 Jun;11(3):262-70 - PubMed
  15. J Cell Sci. 2009 Dec 1;122(Pt 23):4393-400 - PubMed
  16. Curr Opin Virol. 2012 Dec;2(6):784-92 - PubMed
  17. EMBO J. 1999 Feb 15;18(4):1081-91 - PubMed
  18. Nature. 2007 Mar 1;446(7131):92-6 - PubMed
  19. Nature. 2008 Aug 14;454(7206):890-3 - PubMed
  20. Antiviral Res. 2010 Aug;87(2):111-24 - PubMed
  21. Nat Rev Microbiol. 2004 Oct;2(10):789-801 - PubMed
  22. Cell. 2004 Apr 30;117(3):285-97 - PubMed
  23. J Virol. 2003 Nov;77(22):12022-32 - PubMed
  24. Genes Dev. 2005 Feb 15;19(4):445-52 - PubMed
  25. Mol Biol Cell. 2002 Dec;13(12):4371-87 - PubMed
  26. Nat Immunol. 2004 Jan;5(1):81-7 - PubMed
  27. Nat Cell Biol. 2013 May;15(5):461-71 - PubMed
  28. Mol Biol Cell. 1999 Nov;10(11):3825-34 - PubMed
  29. Nature. 2008 Aug 28;454(7208):1142-6 - PubMed
  30. Gastroenterology. 2011 Apr;140(4):1261-1271.e1 - PubMed
  31. Biochem Cell Biol. 2006 Dec;84(6):960-78 - PubMed
  32. Antiviral Res. 2010 Feb;85(2):328-45 - PubMed
  33. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4834-9 - PubMed
  34. Nat Rev Mol Cell Biol. 2008 Dec;9(12):944-57 - PubMed
  35. Blood. 2008 Nov 15;112(10):4268-75 - PubMed
  36. Anal Biochem. 1996 Jan 15;233(2):221-7 - PubMed
  37. Chem Biol. 2006 Sep;13(9):965-72 - PubMed
  38. Nature. 2009 Apr 23;458(7241):1047-50 - PubMed
  39. Vet Microbiol. 2010 Jan 27;140(3-4):281-6 - PubMed
  40. Biochemistry. 2005 Sep 13;44(36):12149-59 - PubMed
  41. J Virol. 2001 Mar;75(6):2653-9 - PubMed
  42. Exp Cell Res. 2013 Nov 1;319(18):2759-69 - PubMed
  43. Virus Res. 2010 Nov;153(2):179-96 - PubMed
  44. Cell Host Microbe. 2011 Aug 18;10(2):97-104 - PubMed
  45. J Clin Virol. 2006 Mar;35(3):233-43 - PubMed
  46. J Virol. 1990 May;64(5):2041-6 - PubMed
  47. Science. 2011 Nov 25;334(6059):1081-6 - PubMed
  48. Virology. 2012 Feb 5;423(1):1-5 - PubMed
  49. J Cell Biol. 2005 Oct 10;171(1):111-20 - PubMed
  50. J Biol Chem. 2008 Mar 21;283(12):7445-54 - PubMed
  51. PLoS Pathog. 2007 Jun;3(6):e89 - PubMed
  52. Annu Rev Physiol. 2007;69:69-85 - PubMed
  53. Biochim Biophys Acta. 2010 Mar;1803(3):424-34 - PubMed
  54. Virology. 2007 Oct 10;367(1):212-21 - PubMed
  55. Mol Cell. 2010 Oct 22;40(2):238-52 - PubMed
  56. Pharmacogenomics. 2006 Apr;7(3):299-309 - PubMed
  57. Cell Res. 2012 Feb;22(2):346-59 - PubMed

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