1887

Journal of General Virology header logo

Volume 102, Issue 9

A natural variant in ANP32B impairs influenza virus replication in human cells Open Access

Abstract

Viruses require host factors to support their replication, and genetic variation in such factors can affect susceptibility to infectious disease. Influenza virus replication in human cells relies on ANP32 proteins, which are involved in assembly of replication-competent dimeric influenza virus polymerase (FluPol) complexes. Here, we investigate naturally occurring single nucleotide variants (SNV) in the human and genes. We note that variant rs182096718 in is found at a higher frequency than other variants in either gene. This SNV results in a D130A substitution in ANP32B, which is less able to support FluPol activity than wild-type ANP32B and binds FluPol with lower affinity. Interestingly, ANP32B-D130A exerts a dominant negative effect over wild-type ANP32B and interferes with the functionally redundant paralogue ANP32A. FluPol activity and virus replication are attenuated in CRISPR-edited cells expressing wild-type ANP32A and mutant ANP32B-D130A. We propose a model in which the D130A mutation impairs FluPol dimer formation, thus resulting in compromised replication. We suggest that both homozygous and heterozygous carriers of rs182096718 may have some genetic protection against influenza viruses.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): ANP32B , dominant negative , Influenza virus , polymerase dimer and single nucleotide variant
Funding
This study was supported by the:
  • biotechnology and biological sciences research council (Award bb/k002456/1)
    • Principle Award Recipient: CarolM. Sheppard
  • ukri future leaders fellowship (Award mr/s032304/1)
    • Principle Award Recipient: VanessaSancho-Shimizu
  • biotechnology and biological sciences research council (Award bb/r013071/1)
    • Principle Award Recipient: ThomasP. Peacock
  • wellcome trust (Award 200187/z/15/z)
    • Principle Award Recipient: RebeccaFrise
  • wellcome trust (Award 209213/z/17/z)
    • Principle Award Recipient: LauryBaillon
  • biotechnology and biological sciences research council (Award bb/k002456/1)
    • Principle Award Recipient: WendyS Barclay
  • wellcome trust (Award 205100)
    • Principle Award Recipient: WendyS Barclay
  • wellcome trust (Award 205100)
    • Principle Award Recipient: CarolM. Sheppard
  • imperial college president's scholarship
    • Principle Award Recipient: EccoStaller
© 2021 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001664
2021-09-15
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/jgv/102/9/jgv001664.html?itemId=/content/journal/jgv/10.1099/jgv.0.001664&mimeType=html&fmt=ahah

References

  1. Ciancanelli MJ, Abel L, Zhang SY, Casanova JL. Host genetics of severe influenza: from mouse Mx1 to human IRF7. Curr Opin Immunol 2016; 38:109–120 [View Article] [PubMed]
     [Google Scholar]
  2. Karlsson EK, Kwiatkowski DP, Sabeti PC. Natural selection and infectious disease in human populations. Nat Rev Genet 2014; 15:379–393 [View Article] [PubMed]
     [Google Scholar]
  3. Pittman KJ, Glover LC, Wang L, Ko DC. The legacy of past pandemics: common human mutations that protect against infectious disease. PLoS Pathog 2016; 12: [View Article]
     [Google Scholar]
  4. Zhang Q. Human genetics of life-threatening influenza pneumonitis. Hum Genet 2020; 139:941–948 [View Article] [PubMed]
     [Google Scholar]
  5. Carrington M, Dean M, Martin MP. Genetics of HIV-1 infection: Chemokine receptor CCR5 polymorphism and its consequences. Hum Mol Genet 1999; 8:1939–1945 [View Article] [PubMed]
     [Google Scholar]
  6. Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G et al. Ebola virus entry requires the cholesterol transporter Niemann–Pick C1. Nature 2011; 477:340–343 [View Article] [PubMed]
     [Google Scholar]
  7. Kondoh T, Letko M, Munster VJ, Manzoor R, Maruyama J et al. Single-nucleotide polymorphisms in human NPC1 influence filovirus entry into cells. J Infect Dis 2018; 218:S397–s402 [View Article] [PubMed]
     [Google Scholar]
  8. Lindesmith L, Moe C, Marionneau S, Ruvoen N, Jiang X et al. Human susceptibility and resistance to Norwalk virus infection. Nat Med 2003; 9:548–553 [View Article] [PubMed]
     [Google Scholar]
  9. Thorven M, Grahn A, Hedlund K-O, Johansson H, Wahlfrid C et al. A homozygous nonsense mutation (428G→A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (GGII) infections. J Virol 2005; 79:15351–15355 [View Article] [PubMed]
     [Google Scholar]
  10. Everitt AR, Clare S, Pertel T, John SP, Wash RS et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature 2012; 484:519–523 [View Article] [PubMed]
     [Google Scholar]
  11. Lee N, Cao B, Ke C, Lu H, Hu Y et al. IFITM3, TLR3, and CD55 gene SNPs and cumulative genetic risks for severe outcomes in Chinese patients with H7N9/H1N1pdm09 influenza. J Infect Dis 2017; 216:97–104 [View Article] [PubMed]
     [Google Scholar]
  12. Zhang Y-H, Zhao Y, Li N, Peng Y-C, Giannoulatou E et al. Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals. Nat Commun 2013; 4:1418 [View Article] [PubMed]
     [Google Scholar]
  13. Mills TC, Rautanen A, Elliott KS, Parks T, Naranbhai V et al. IFITM3 and susceptibility to respiratory viral infections in the community. J Infect Dis 2014; 209:1028–1031 [View Article] [PubMed]
     [Google Scholar]
  14. Randolph AG, Yip WK, Allen EK, Rosenberger CM, Agan AA et al. Evaluation of IFITM3 rs12252 association with severe pediatric influenza infection. J Infect Dis 2017; 216:14–21 [View Article] [PubMed]
     [Google Scholar]
  15. Prabhu SS, Chakraborty TT, Kumar N, Banerjee I. Association between IFITM3 rs12252 polymorphism and influenza susceptibility and severity: A meta-analysis. Gene 2018; 674:70–79 [View Article] [PubMed]
     [Google Scholar]
  16. Allen EK, Randolph AG, Bhangale T, Dogra P, Ohlson M et al. SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. Nat Med 2017; 23:975–983 [View Article] [PubMed]
     [Google Scholar]
  17. Graf L, Dick A, Sendker F, Barth E, Marz M et al. Effects of allelic variations in the human myxovirus resistance protein A on its antiviral activity. J Biol Chem 2018; 293:3056–3072 [View Article] [PubMed]
     [Google Scholar]
  18. Chatzopoulou F, Gioula G, Kioumis I, Chatzidimitriou D, Exindari M. Identification of complement-related host genetic risk factors associated with influenza A(H1N1)pdm09 outcome: challenges ahead. Med Microbiol Immunol 2019; 208:631–640 [View Article] [PubMed]
     [Google Scholar]
  19. Herrera-Ramos E, Lopez-Rodriguez M, Ruiz-Hernandez JJ, Horcajada JP, Borderias L et al. Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection. Crit Care 2014; 18:R127 [View Article] [PubMed]
     [Google Scholar]
  20. Cheng Z, Zhou J, To KK-W, Chu H, Li C et al. Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A(H1N1) influenza and A(H7N9) influenza. J Infect Dis 2015; 212:1214–1221 [View Article] [PubMed]
     [Google Scholar]
  21. Sologuren I, Martinez-Saavedra MT, Sole-Violan J, de Borges de Oliveira E, Betancor E et al. Lethal influenza in two related adults with inherited GATA2 deficiency. J Clin Immunol 2018; 38:513–526 [View Article] [PubMed]
     [Google Scholar]
  22. Bravo García-Morato M, Calvo Apalategi A, Bravo-Gallego LY, Blázquez Moreno A, Simón-Fuentes M et al. Impaired control of multiple viral infections in a family with complete IRF9 deficiency. J Allergy Clin Immunol 2019; 144:309–312 [View Article] [PubMed]
     [Google Scholar]
  23. Ciancanelli MJ, Huang S, Luthra P, Garner H, Itan Y et al. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 2015; 348:448–453 [View Article] [PubMed]
     [Google Scholar]
  24. Hernandez N, Melki I, Jing H, Habib T, Huang SSY et al. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med 2018; 215:2567–2585 [View Article] [PubMed]
     [Google Scholar]
  25. Esposito S, Molteni CG, Giliani S, Mazza C, Scala A et al. Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children. Virol J 2012; 9:270 [View Article] [PubMed]
     [Google Scholar]
  26. Hidaka F, Matsuo S, Muta T, Takeshige K, Mizukami T et al. A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy. Clin Immunol 2006; 119:188–194 [View Article] [PubMed]
     [Google Scholar]
  27. Lim HK, Huang SXL, Chen J, Kerner G, Gilliaux O et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med 2019; 216:2038–2056 [View Article] [PubMed]
     [Google Scholar]
  28. Chen Y, Zhou J, Cheng Z, Yang S, Chu H et al. Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9. Sci Rep 2015; 5:8517 [View Article] [PubMed]
     [Google Scholar]
  29. Nogales A, L DeDiego M. Host single nucleotide polymorphisms modulating influenza A virus disease in humans. Pathogens 2019; 8: [View Article] [PubMed]
     [Google Scholar]
  30. Fodor E, Te Velthuis AJW. Structure and function of the influenza virus transcription and replication machinery. Cold Spring Harb Perspect Med 2019; 10: [View Article] [PubMed]
     [Google Scholar]
  31. Wandzik JM, Kouba T, Cusack S. Structure and function of influenza polymerase. Cold Spring Harb Perspect Med 2020a038372 [View Article]
     [Google Scholar]
  32. Staller E, Barclay WS. Host cell factors that interact with influenza virus Ribonucleoproteins. Cold Spring Harb Perspect Med 2020 [View Article] [PubMed]
     [Google Scholar]
  33. Carrique L, Fan H, Walker AP, Keown JR, Sharps J et al. Host ANP32A mediates the assembly of the influenza virus replicase. Nature 2020; 587:638–643 [View Article] [PubMed]
     [Google Scholar]
  34. Chang S, Sun D, Liang H, Wang J, Li J et al. Cryo-EM structure of influenza virus RNA polymerase complex at 4.3 Å resolution. Mol Cell 2015; 57:925–935 [View Article] [PubMed]
     [Google Scholar]
  35. Chen KY, Santos Afonso ED, Enouf V, Isel C, Naffakh N. Influenza virus polymerase subunits co-evolve to ensure proper levels of dimerization of the heterotrimer. PLoS Pathog 2019; 15:e1008034 [View Article] [PubMed]
     [Google Scholar]
  36. Fan H, Walker AP, Carrique L, Keown JR, Martin S et al. Structures of influenza A virus RNA polymerase offer insight into viral genome replication. Nature 2019; 573:287–290 [View Article] [PubMed]
     [Google Scholar]
  37. Peng Q, Liu Y, Peng R, Wang M, Yang W et al. Structural insight into RNA synthesis by influenza D polymerase. Nat Microbiol 2019; 4:1750–1759 [View Article] [PubMed]
     [Google Scholar]
  38. Long JS, Giotis ES, Moncorge O, Frise R, Mistry B et al. Species difference in ANP32A underlies influenza A virus polymerase host restriction. Nature 2016; 529:101–104 [View Article] [PubMed]
     [Google Scholar]
  39. Staller E, Sheppard CM, Neasham PJ, Mistry B, Peacock TP et al. ANP32 proteins are essential for influenza virus replication in human cells. J Virol 2019; 93:17 [View Article]
     [Google Scholar]
  40. Zhang H, Zhang Z, Wang Y, Wang M, Wang X et al. Fundamental contribution and host range determination of ANP32A and ANP32B in influenza A virus polymerase activity. J Virol 2019; 93:13 [View Article]
     [Google Scholar]
  41. Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E et al. The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013; 45:580–585 [View Article] [PubMed]
     [Google Scholar]
  42. Reilly PT, Yu Y, Hamiche A, Wang L. Cracking the ANP32 whips: important functions, unequal requirement, and hints at disease implications. Bioessays 2014; 36:1062–1071 [View Article] [PubMed]
     [Google Scholar]
  43. Kleiner RE, Hang LE, Molloy KR, Chait BT, Kapoor TM. A chemical proteomics approach to reveal direct protein-protein interactions in living cells. Cell Chem Biol 2018; 25:110–120 [View Article] [PubMed]
     [Google Scholar]
  44. Obri A, Ouararhni K, Papin C, Diebold ML, Padmanabhan K et al. ANP32E is a histone chaperone that removes H2A.Z from chromatin. Nature 2014; 505:648–653 [View Article] [PubMed]
     [Google Scholar]
  45. Saavedra F, Rivera C, Rivas E, Merino P, Garrido D et al. PP32 and SET/TAF-Iβ proteins regulate the acetylation of newly synthesized histone H4. Nucleic Acids Res 2017; 45:11700–11710 [View Article] [PubMed]
     [Google Scholar]
  46. Tochio N, Umehara T, Munemasa Y, Suzuki T, Sato S et al. Solution structure of histone chaperone ANP32B: interaction with core histones H3-H4 through its acidic concave domain. J Mol Biol 2010; 401:97–114 [View Article] [PubMed]
     [Google Scholar]
  47. Camacho-Zarco AR, Kalayil S, Maurin D, Salvi N, Delaforge E et al. Molecular basis of host-adaptation interactions between influenza virus polymerase PB2 subunit and ANP32A. Nat Commun 2020; 11:3656 [View Article] [PubMed]
     [Google Scholar]
  48. Huyton T, Wolberger C. The crystal structure of the tumor suppressor protein pp32 (Anp32a): structural insights into Anp32 family of proteins. Protein Sci 2007; 16:1308–1315 [View Article] [PubMed]
     [Google Scholar]
  49. Long JS, Idoko-Akoh A, Mistry B, Goldhill D, Staller E et al. Species specific differences in use of ANP32 proteins by influenza A virus. eLife 2019; 8:e45066 [View Article] [PubMed]
     [Google Scholar]
  50. Peacock TP, Sheppard CM, Staller E, Frise R, Swann OC et al. Mammalian ANP32A and ANP32B proteins drive alternative avian influenza virus polymerase adaptations. bioRxiv 2020; 2020.09.03.282384: [View Article]
     [Google Scholar]
  51. Mistry B, Long JS, Schreyer J, Staller E, Sanchez-David RY et al. Elucidating the interactions between influenza virus polymerase and host factor ANP32A. J Virol 2020; 94:e01353-01319 [View Article] [PubMed]
     [Google Scholar]
  52. Kaltenegger E, Ober D. Paralogue interference affects the dynamics after gene duplication. Trends Plant Sci 2015; 20:814–821 [View Article] [PubMed]
     [Google Scholar]
  53. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J et al. Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. bioRxiv 2019; 531210: [View Article]
     [Google Scholar]
  54. Hong R, Macfarlan T, Kutney SN, Seo S-B, Mukai Y et al. The identification of phosphorylation sites of PP32 and biochemical purification of a cellular PP32-kinase. Biochemistry 2004; 43:10157–10165 [View Article] [PubMed]
     [Google Scholar]
  55. Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. bioRxiv 2019; 563866: [View Article]
     [Google Scholar]
  56. Peacock TP, Swann OC, Staller E, Leung PB, Goldhill DH et al. Swine ANP32A supports avian influenza virus polymerase. bioRxiv 2020; 2020.01.24.916916: [View Article]
     [Google Scholar]
  57. Beck S, Zickler M, Pinho Dos Reis V, Günther T, Grundhoff A et al. ANP32B deficiency protects mice from lethal influenza a virus challenge by dampening the host immune response. Front Immunol 2020; 11:450 [View Article] [PubMed]
     [Google Scholar]
  58. Liang L, Jiang L, Li J, Zhao Q, Wang J et al. Low polymerase activity attributed to PA drives the acquisition of the PB2 E627K mutation of H7N9 avian influenza virus in mammals. mBio 2019; 10: [View Article] [PubMed]
     [Google Scholar]
  59. Fries B, Heukeshoven J, Hauber I, Gruttner C, Stocking C et al. Analysis of nucleocytoplasmic trafficking of the HuR ligand APRIL and its influence on CD83 expression. J Biol Chem 2007; 282:4504–4515 [View Article] [PubMed]
     [Google Scholar]
  60. Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Kersey JH et al. In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. J Natl Cancer Inst 1973; 51:1417–1423 [View Article] [PubMed]
     [Google Scholar]
  61. Graham FL, Smiley J, Russell WC, Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol 1977; 36:59–74 [View Article] [PubMed]
     [Google Scholar]
  62. Lin YC, Boone M, Meuris L, Lemmens I, Van Roy N et al. Genome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations. Nat Commun 2014; 5:4767 [View Article] [PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001664
Loading
A natural variant in ANP32B impairs influenza virus replication in human cells
J. Gen. Virol. 102, 001664 (2021); https://doi.org/10.1099/jgv.0.001664
/content/journal/jgv/10.1099/jgv.0.001664
/content/journal/jgv/10.1099/jgv.0.001664
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error