. doi: 10.1016/j.virs.2024.01.003
Citation: Lei Yu, Xinjin Liu, Xiaoqin Wei, Junrui Ren, Xueyun Wang, Shuwen Wu, Ke Lan. C1QTNF5 is a novel attachment factor that facilitates the entry of influenza A virus .VIROLOGICA SINICA, 2024, 39(2) : 277-289.  http://dx.doi.org/10.1016/j.virs.2024.01.003

C1QTNF5是一种新型吸附因子促进甲型流感病毒进入

  • 甲型流感病毒(Influenza A virus, IAV)通过结合细胞表面唾液酸(Sialic acid,SA)受体进入宿主细胞,这是启动感染、传播和致病的关键步骤。了解导致IAV高效进入人类细胞的因素将有助于阐明病毒进入和致病的机制,并提供新的干预靶点。在本研究中,我们报道了一种新的膜蛋白C1QTNF5,它与IAV的血凝素(Hemagglutinin,HA)蛋白结合并在体内外促进IAV感染。鉴定出IAV血凝素的HA1区域是与C1QTNF5蛋白相互作用的关键区域,而C1QTNF5主要通过其N端(1- 103aa)与血凝素相互作用。此外,我们进一步发现过表达C1QTNF5可促进IAV进入,而阻断C1QTNF5和IAV血凝素之间的相互作用极大地抑制了病毒的进入。然而,在唾液酸缺陷的CHO-Lec2细胞中,C1QTNF5不能作为独立受体介导IAV感染,而是促进IAV附着在这些细胞上,这表明C1QTNF5是IAV的重要吸附因子。这项工作揭示了C1QTNF5作为一种新的IAV吸附因子,为抗病毒策略提供了新的视角。

C1QTNF5 is a novel attachment factor that facilitates the entry of influenza A virus

  • Influenza A virus (IAV) binds sialic acid receptors on the cell surface to enter the host cells, which is the key step in initiating infection, transmission and pathogenesis. Understanding the factors that contribute to the highly efficient entry of IAV into human cells will help elucidate the mechanism of viral entry and pathogenicity, and provide new targets for intervention. In the present study, we reported a novel membrane protein, C1QTNF5, which binds to the hemagglutinin protein of IAV and promotes IAV infection in vitro and in vivo. We found that the HA1 region of IAV hemagglutinin is critical for the interaction with C1QTNF5 protein, and C1QTNF5 interacts with hemagglutinin mainly through its N-terminus (1–103 aa). In addition, we further demonstrated that overexpression of C1QTNF5 promotes IAV entry, while blocking the interaction between C1QTNF5 and IAV hemagglutinin greatly inhibits viral entry. However, C1QTNF5 does not function as a receptor to mediate IAV infection in sialic acid-deficient CHO-Lec2 cells, but promotes IAV to attach to these cells, suggesting that C1QTNF5 is an important attachment factor for IAV. This work reveals C1QTNF5 as a novel IAV attachment factor and provides a new perspective for antiviral strategies.

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    1. Amraei, R., Xia, C.S., Olejnik, J., White, M.R., Napoleon, M.A., Lotfollahzadeh, S., Hauser, B.M., Schmidt, A.G., Chitalia, V., Muhlberger, E., Costello, C.E., Rahimi, N., 2022. Extracellular vimentin is an attachment factor that facilitates SARS-CoV-2 entry into human endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 119, e2113874119.

    2. Ayyagari, R., Mandal, M.N., Karoukis, A.J., Chen, L., McLaren, N.C., Lichter, M., Wong, D.T., Hitchcock, P.F., Caruso, R.C., Moroi, S.E., Maumenee, I.H., Sieving, P.A., 2005. Late-onset macular degeneration and long anterior lens zonules result from a CTRP5 gene mutation. Invest. Ophthalmol. Vis. Sci. 46, 3363-3371.

    3. Bouvier, N.M., Palese, P., 2008. The biology of influenza viruses. Vaccine 26, D49-D53.

    4. Cantuti-Castelvetri, L., Ojha, R., Pedro, L.D., Djannatian, M., Franz, J., Kuivanen, S., van der Meer, F., Kallio, K., Kaya, T., Anastasina, M., Smura, T., Levanov, L., Szirovicza, L., Tobi, A., Kallio-Kokko, H., Osterlund, P., Joensuu, M., Meunier, F.A., Butcher, S.J., Winkler, M.S., Mollenhauer, B., Helenius, A., Gokce, O., Teesalu, T., Hepojoki, J., Vapalahti, O., Stadelmann, C., Balistreri, G., Simons, M., 2020. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 370, 856-860.

    5. Chen, J., Liu, J., Chen, Z., Feng, D., Zhu, C., Fan, J., Zhang, S., Zhang, X., Xu, J., 2022. Nonmuscle myosin IIA promotes the internalization of influenza A virus and regulates viral polymerase activity through interacting with nucleoprotein in human pulmonary cells. Virol Sin 38, 128-141.

    6. Chu, V.C., Whittaker, G.R., 2004. Influenza virus entry and infection require host cell N-linked glycoprotein. Proc. Natl. Acad. Sci. U. S. A. 101, 18153-18158.

    7. Copeland, C.S., Doms, R.W., Bolzau, E.M., Webster, R.G., Helenius, A., 1986. Assembly of Influenza Hemagglutinin Trimers and Its Role in Intracellular-Transport. J. Cell. Biol. 103, 1179-1191.

    8. Cox, N.J., Subbarao, K., 1999. Influenza. Lancet 354, 1277-1282.

    9. Eckhardt, M., Gotza, B., Gerardy-Schahn, R., 1998. Mutants of the CMP-sialic acid transporter causing the Lec2 phenotype. J. Biol. Chem. 273, 20189-20195.

    10. Eslami, N., Aghbash, P.S., Shamekh, A., Entezari-Maleki, T., Nahand, J.S., Sales, A.J., Baghi, H.B., 2022. SARS-CoV-2:Receptor and Co-receptor Tropism Probability. Curr Microbiol 79, 133.

    11. Fislova, T., Gocnik, M., Sladkova, T., Durmanova, V., Rajcani, J., Vareckova, E., Mucha, V., Kostolansky, F., 2009. Multiorgan distribution of human influenza A virus strains observed in a mouse model. Arch Virol 154, 409-419.

    12. Gamblin, S.J., Vachieri, S.G., Xiong, X., Zhang, J., Martin, S.R., Skehel, J.J., 2021. Hemagglutinin Structure and Activities. Cold. Spring. Harb. Perspect. Med. 11, a038638.

    13. Gething, M.J., Mccammon, K., Sambrook, J., 1986. Expression of Wild-Type and Mutant Forms of Influenza Hemagglutinin-the Role of Folding in Intracellular-Transport. Cell 46, 939-950.

    14. Gottschalk, A., 1959. Chemistry of virus receptors, in:Burnet, F.M., Stanley, W.M. (ed), The viruses:biochemical, biological and biophysical properties. Vol.3, New York, pp.51-61.

    15. Grove, J., Marsh, M., 2011. The cell biology of receptor-mediated virus entry. J. Cell. Biol. 195, 1071-1082.

    16. Hause, B.M., Collin, E.A., Liu, R., Huang, B., Sheng, Z., Lu, W., Wang, D., Nelson, E.A., Li, F., 2014. Characterization of a novel influenza virus in cattle and Swine:proposal for a new genus in the Orthomyxoviridae family. mBio 5, e00031-00014.

    17. Hayward, C., Shu, X., Cideciyan, A.V., Lennon, A., Barran, P., Zareparsi, S., Sawyer, L., Hendry, G., Dhillon, B., Milam, A.H., Luthert, P.J., Swaroop, A., Hastie, N.D., Jacobson, S.G., Wright, A.F., 2003. Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration:a genetic model for age-related macular degeneration. Hum. Mol. Genet. 12, 2657-2667.

    18. He, Q.Q., Ren, S., Xia, Z.C., Cheng, Z.K., Peng, N.F., Zhu, Y., 2018. Fibronectin Facilitates Enterovirus 71 Infection by Mediating Viral Entry. J. Virol. 92, e02251-17.

    19. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.H., Nitsche, A., Muller, M.A., Drosten, C., Pohlmann, S., 2020. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181, 271-280.

    20. Javanian, M., Barary, M., Ghebrehewet, S., Koppolu, V., Vasigala, V., Ebrahimpour, S., 2021. A brief review of influenza virus infection. J. Med. Virol. 93, 4638-4646.

    21. Karakus, U., Pohl, M.O., Stertz, S., 2020. Breaking the Convention:Sialoglycan Variants, Coreceptors, and Alternative Receptors for Influenza A Virus Entry. J. Virol. 94, e01357-19.

    22. Kenney, A.D., McMichael, T.M., Imas, A., Chesarino, N.M., Zhang, L., Dorn, L.E., Wu, Q., Alfaour, O., Amari, F., Chen, M., Zani, A., Chemudupati, M., Accornero, F., Coppola, V., Rajaram, M.V.S., Yount, J.S., 2019. IFITM3 protects the heart during influenza virus infection. Proc. Natl. Acad. Sci. U. S. A. 116, 18607-18612.

    23. Killingley, B., Nguyen-Van-Tam, J., 2013. Routes of influenza transmission. Influenza. Other. Respir. Viruses. 7, 42-51.

    24. Lei, C.Q., Wu, X., Zhong, X., Jiang, L., Zhong, B., Shu, H.B., 2019. USP19 Inhibits TNF-alpha- and IL-1beta-Triggered NF-kappaB Activation by Deubiquitinating TAK1. J. Immunol. 203, 259-268.

    25. Lei, X., Rodriguez, S., Petersen, P.S., Seldin, M.M., Bowman, C.E., Wolfgang, M.J., Wong, G.W., 2016. Loss of CTRP5 improves insulin action and hepatic steatosis. Am. J. Physiol. Endocrinol. Metab. 310, E1036-E1052.

    26. Li, W.H., Moore, M.J., Vasilieva, N., Sui, J.H., Wong, S.K., Berne, M.A., Somasundaran, M., Sullivan, J.L., Luzuriaga, K., Greenough, T.C., Choe, H., Farzan, M., 2003. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450-454.

    27. Londrigan, S.L., Turville, S.G., Tate, M.D., Deng, Y.M., Brooks, A.G., Reading, P.C., 2011. N-Linked Glycosylation Facilitates Sialic Acid-Independent Attachment and Entry of Influenza A Viruses into Cells Expressing DC-SIGN or L-SIGN. J. Virol. 85, 2990-3000.

    28. Maginnis, M.S., 2018. Virus-Receptor Interactions:The Key to Cellular Invasion. J. Mol. Biol. 430, 2590-2611.

    29. Mandal, M.N., Vasireddy, V., Reddy, G.B., Wang, X., Moroi, S.E., Pattnaik, B.R., Hughes, B.A., Heckenlively, J.R., Hitchcock, P.F., Jablonski, M.M., Ayyagari, R., 2006. CTRP5 is a membrane-associated and secretory protein in the RPE and ciliary body and the S163R mutation of CTRP5 impairs its secretion. Invest. Ophthalmol. Vis. Sci. 47, 5505-5513.

    30. Matrosovich, M., Herrler, G., Klenk, H.D., 2015. Sialic Acid Receptors of Viruses. Top. Curr. Chem 367, 1-28.

    31. Moore, J.P., 1997. Co-receptors for HIV-1 entry. Curr. Opin. Immunol. 9, 551-562.

    32. Nakagawa, H., Noma, H., Kotake, O., Motohashi, R., Yasuda, K., Shimura, M., 2017. Optic neuritis and acute anterior uveitis associated with influenza A infection:a case report. Int. Med. Case. Rep. J. 10, 1-5.

    33. Park, J.E., Ryu, Y., 2018. Transmissibility and severity of influenza virus by subtype. Infect. Genet. Evol. 65, 288-292.

    34. Park, S.Y., Choi, J.H., Ryu, H.S., Pak, Y.K., Park, K.S., Lee, H.K., Lee, W., 2009. C1q tumor necrosis factor alpha-related protein isoform 5 is increased in mitochondrial DNA-depleted myocytes and activates AMP-activated protein kinase. J. Biol. Chem. 284, 27780-27789.

    35. Paules, C., Subbarao, K., 2017. Influenza. Lancet 390, 697-708.

    36. Raj, V.S., Mou, H.H., Smits, S.L., Dekkers, D.H.W., Muller, M.A., Dijkman, R., Muth, D., Demmers, J.A.A., Zaki, A., Fouchier, R.A.M., Thiel, V., Drosten, C., Rottier, P.J.M., Osterhaus, A.D.M.E., Bosch, B.J., Haagmans, B.L., 2013. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 495, 251-254.

    37. Sasaki, M., Anindita, P.D., Ito, N., Sugiyama, M., Carr, M., Fukuhara, H., Ose, T., Maenaka, K., Takada, A., Hall, W.W., Orba, Y., Sawa, H., 2018. The Role of Heparan Sulfate Proteoglycans as an Attachment Factor for Rabies Virus Entry and Infection. J. Infect. Dis. 217, 1740-1749.

    38. Schaffler, A., Buechler, C., 2012. CTRP family:linking immunity to metabolism. Trends. Endocrinol. Metab. 23, 194-204.

    39. Sieczkarski, S.B., Whittaker, G.R., 2005. Viral entry. Curr. Top. Microbiol.Immunol. 285, 1-23.

    40. Smith, A.E., Helenius, A., 2004. How viruses enter animal cells. Science 304, 237-242.

    41. Sriwilaijaroen, N., Suzuki, Y., 2012. Molecular basis of the structure and function of H1 hemagglutinin of influenza virus. Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci. 88, 226-249.

    42. Steinhauer, D.A., 1999. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 258, 1-20.

    43. Suzuki, Y., 2005. Sialobiology of influenza:molecular mechanism of host range variation of influenza viruses. Biol. Pharm. Bull. 28, 399-408.

    44. Tu, X.Y., Palczewski, K., 2012. Crystal structure of the globular domain of C1QTNF5:Implications for late-onset retinal macular degeneration. J. Struct. Biol. 180, 439-446.

    45. Wang, J., Qiao, L., Hou, Z., Luo, G., 2017. TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection. J. Virol. 91, e01583-16.

    46. Wang, R., Zhu, Y., Lin, X., Ren, C., Zhao, J., Wang, F., Gao, X., Xiao, R., Zhao, L., Chen, H., Jin, M., Ma, W., Zhou, H., 2019. Influenza M2 protein regulates MAVS-mediated signaling pathway through interacting with MAVS and increasing ROS production. Autophagy 15, 1163-1181.

    47. Wang, S.F., Huang, J.C., Lee, Y.M., Liu, S.J., Chan, Y.J., Chau, Y.P., Chong, P., Chen, Y.M., 2008. DC-SIGN mediates avian H5N1 influenza virus infection in cis and in trans. Biochem. Biophys. Res. Commun. 373, 561-566.

    48. Wang, X.B., Zheng, T.Y., Lin, L.L., Zhang, Y.N., Peng, X.R., Yan, Y., Lei, J., Zhou, J.Y., Hu, B.L., 2020. Influenza A Virus Induces Autophagy by Its Hemagglutinin Binding to Cell Surface Heat Shock Protein 90AA1. Front. Microbiol. 11, 566348.

    49. Wong, G.W., Krawczyk, S.A., Kitidis-Mitrokostas, C., Revett, T., Gimeno, R., Lodish, H.F., 2008. Molecular, biochemical and functional characterizations of C1q/TNF family members:adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions. Biochem. J. 416, 161-177.

    50. Yan, H., Zhong, G.C., Xu, G.W., He, W.H., Jing, Z.Y., Gao, Z.C., Huang, Y., Qi, Y.H., Peng, B., Wang, H.M., Fu, L.R., Song, M., Chen, P., Gao, W.Q., Ren, B.J., Sun, Y.Y., Cai, T., Feng, X.F., Sui, J.H., Li, W.H., 2012. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 1, e00049.

    51. Yang, C., Liu, X., Gao, Q., Cheng, T., Xiao, R., Ming, F., Zhang, S., Jin, M., Chen, H., Ma, W., Zhou, H., 2018. The Nucleolar Protein LYAR Facilitates Ribonucleoprotein Assembly of Influenza A Virus. J. Virol. 92, e01042-01018.

    52. Yuan, F., Li, D.D., Li, C.Y., Zhang, Y.N., Song, H., Li, S.H., Deng, H.K., Gao, G.F., Zheng, A.H., 2021. ADAM17 is an essential attachment factor for classical swine fever virus. PLoS Pathog. 17, e1009393.

    53. Zhang, J., Huang, F., Tan, L., Bai, C., Chen, B., Liu, J., Liang, J., Liu, C., Zhang, S., Lu, G., Chen, Y., Zhang, H., 2016. Host Protein Moloney Leukemia Virus 10 (MOV10) Acts as a Restriction Factor of Influenza A Virus by Inhibiting the Nuclear Import of the Viral Nucleoprotein. J. Virol. 90, 3966-3980.

    54. Zheng, H., Ma, L., Gui, R., Lin, X., Ke, X., Jian, X., Ye, C., Chena, Q., 2022. G Protein Subunit β1 Facilitates Influenza A Virus Replication by Promoting the Nuclear Import of PB2. J. Virol. 96, e0049422.

    55. Zhu, P.P., Lv, C.F., Fang, C.X., Peng, X., Sheng, H., Xiao, P., Ojha, N.K., Yan, Y., Liao, M., Zhou, J.Y., 2020. Heat Shock Protein Member 8 Is an Attachment Factor for Infectious Bronchitis Virus. Front. Microbiol. 11, 1630.

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    C1QTNF5 is a novel attachment factor that facilitates the entry of influenza A virus

      Corresponding author: Shuwen Wu, shuwenwu@whu.edu.cn
      Corresponding author: Ke Lan, klan@whu.edu.cn
    • a. State Key Laboratory of Virology, Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan, 430072, China;
    • b. Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430072, China;
    • c. Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China

    Abstract: Influenza A virus (IAV) binds sialic acid receptors on the cell surface to enter the host cells, which is the key step in initiating infection, transmission and pathogenesis. Understanding the factors that contribute to the highly efficient entry of IAV into human cells will help elucidate the mechanism of viral entry and pathogenicity, and provide new targets for intervention. In the present study, we reported a novel membrane protein, C1QTNF5, which binds to the hemagglutinin protein of IAV and promotes IAV infection in vitro and in vivo. We found that the HA1 region of IAV hemagglutinin is critical for the interaction with C1QTNF5 protein, and C1QTNF5 interacts with hemagglutinin mainly through its N-terminus (1–103 aa). In addition, we further demonstrated that overexpression of C1QTNF5 promotes IAV entry, while blocking the interaction between C1QTNF5 and IAV hemagglutinin greatly inhibits viral entry. However, C1QTNF5 does not function as a receptor to mediate IAV infection in sialic acid-deficient CHO-Lec2 cells, but promotes IAV to attach to these cells, suggesting that C1QTNF5 is an important attachment factor for IAV. This work reveals C1QTNF5 as a novel IAV attachment factor and provides a new perspective for antiviral strategies.

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