Serving the Society Since 1986
Advanced Search
Volume 40 Issue 5
October 2025
    Citation: Haobin Li, Huiyi Guo, Binhao Rong, Haowei Li, Wenjiao Wu, Chan Yang, Shuwen Liu. SNX10 enhances HCoV-OC43 infection by facilitating viral entry and inhibiting virus-triggered autophagy .VIROLOGICA SINICA, 2025, 40(5) : 755-768.  http://dx.doi.org/10.1016/j.virs.2025.07.005
    shu

    SNX10 enhances HCoV-OC43 infection by facilitating viral entry and inhibiting virus-triggered autophagy

    • a. Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China;

    • b. Department of Pharmacy, Jinan University Affiliated Guangdong Second Provincial General Hospital, Guangzhou, 510317, China;

    • c. MOE Key Laboratory of Infectious Diseases Research in South China, MOE Innovation Center for Medical Basic Research on Inflammation and Immune Related Diseases, Southern Medical University, Guangzhou, 510515, China;

    • d. NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Department of Pharmacy, Pingshan Hospital, Southern Medical University, Shenzhen, 518100, China;

    • e. State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou, 510515, China

    • Corresponding author: Shuwen Liu, liusw@smu.edu.cn
    • Received Date: 22 March 2025
      Accepted Date: 07 July 2025
      Available online: 09 July 2025
    • The ongoing coronavirus epidemic, including the novel coronavirus (SARS-CoV-2), continues to pose a significant threat to global public health. Host targets address multiple stages of the viral life cycle and provide diverse opportunities for therapeutic interventions. This study identified sorting nexin 10 (SNX10) as a facilitator of replication of human coronavirus OC43 (HCoV-OC43), underscoring its potential as a novel antiviral target. The knockout of SNX10 significantly suppressed HCoV-OC43 replication both in vivo and in vitro. Immunoprecipitation-mass spectrometry (‌IP-MS) analysis identified the adaptor protein complex 2 subunit μ1 (AP2M1) as a direct interactor of SNX10. Specifically, SNX10 facilitates phosphorylation of the AP2M1, thereby enhancing clathrin-mediated viral endocytosis. Furthermore, subsequent binding and internalization assays revealed that SNX10 knockout significantly inhibits viral entry into host cells. Conversely, the reconstitution of SNX10 fully restored viral entry, thereby confirming the critical and indispensable role of SNX10 in pathogen internalization. Simultaneously, SNX10 was identified as a key factor that promotes endosomal acidification by modulating pH levels, which in turn facilitated the release of the viral genome. Notably, the ablation of SNX10 was found to trigger autophagy activation during infection, thereby maintaining intracellular homeostasis. Additionally, it exerted autonomous antiviral effects through lysosomal degradation pathways. Collectively, these findings demonstrate SNX10 serves as a pivotal regulator of the viral life cycle and underscore its therapeutic potential as a multi-faceted antiviral candidate target capable of simultaneously inhibiting viral internalization, viral genomic release, and host-pathogen equilibrium.
    • 加载中

      1. Agajanian, M.J., Walker, M.P., Axtman, A.D., Ruela-De-Sousa, R.R., Serafin, D.S., Rabinowitz, A.D., Graham, D.M., Ryan, M.B., Tamir, T., Nakamichi, Y., Gammons, M. V., Bennett, J. M., Counago, R. M., Drewry, D. H., Elkins, J. M., Gileadi, C., Gileadi, O., Godoi, P. H., Kapadia, N., Muller, S., Santiago, A.S., Sorrell, F.J., Wells, C.I., Fedorov, O., Willson, T.M., Zuercher, W.J., Major, M. B., 2019. WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop. Cell Rep, 26, 79-93.e78.

      2. Amatya, B., Lee, H., Asico, L.D., Konkalmatt, P., Armando, I., Felder, R.A., Jose, P.A., 2021. SNX-PXA-RGS-PXC Subfamily of SNXs in the Regulation of Receptor-Mediated Signaling and Membrane Trafficking. Int J Mol Sci, 22.

      3. Baggen, J., Thibaut, H.J., Strating, J., Van Kuppeveld, F.J.M., 2018. The life cycle of non-polio enteroviruses and how to target it. Nat Rev Microbiol, 16, 368-381.

      4. Battaglino, R.A., Jha, P., Sultana, F., Liu, W., Morse, L.R., 2019. FKBP12: A partner of Snx10 required for vesicular trafficking in osteoclasts. J Cell Biochem, 120, 13321-13329.

      5. Blanchet, F.P., Mitchell, J.P., Piguet, V., 2012. β-TrCP dependency of HIV-1 Vpu-induced downregulation of CD4 and BST-2/tetherin. Curr HIV Res, 10, 307-314.

      6. Boulant, S., Stanifer, M., Lozach, P.Y., 2015. Dynamics of virus-receptor interactions in virus binding, signaling, and endocytosis. Viruses, 7, 2794-2815.

      7. Brian, D.A., Baric, R.S., 2005. Coronavirus genome structure and replication. Curr Top Microbiol Immunol, 287, 1-30.

      8. Chavoshi, S., Egorova, O., Lacdao, I.K., Farhadi, S., Sheng, Y., Saridakis, V., 2016. Identification of Kaposi Sarcoma Herpesvirus (KSHV) vIRF1 Protein as a Novel Interaction Partner of Human Deubiquitinase USP7. J Biol Chem, 291, 6281-6291.

      9. Chen, L., Yang, L., Li, Y., Liu, T., Yang, B., Liu, L., Wu, R., 2023. Autophagy and Inflammation: Regulatory Roles in Viral Infections. Biomolecules, 13, 1454.

      10. Chen, Y., Liu, Q., Guo, D., 2020. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol, 92, 418-423.

      11. Cocucci, E., Gaudin, R., Kirchhausen, T., 2014. Dynamin recruitment and membrane scission at the neck of a clathrin-coated pit. Mol Biol Cell, 25, 3595-3609.

      12. Dong, X., Yang, Y., Zou, Z., Zhao, Y., Ci, B., Zhong, L., Bhave, M., Wang, L., Kuo, Y.-C., Zang, X., Zhong, R., Aguilera, E.R., Richardson, R.B., Simonetti, B., Schoggins, J.W., Pfeiffer, J.K., Yu, L., Zhang, X., Xie, Y., Schmid, S.L., Xiao, G., Gleeson, P.A., Ktistakis, N.T., Cullen, P.J., Xavier, R.J., Levine, B., 2020. Sorting nexin 5 mediates virus-induced autophagy and immunity. Nature, 589, 456-461.

      13. Fan, T., Liu, B., Yao, H., Chen, X., Yang, H., Guo, S., Wu, B., Li, X., Li, X., Xun, M., Wang, H., 2024. Cathelicidin peptide analogues inhibit EV71 infection through blocking viral entry and uncoating. PLoS Pathog, 20, e1011967.

      14. Fehr, A.R., Perlman, S., 2015. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol, 1282, 1-23.

      15. Ganapathy, A.S., Saha, K., Suchanec, E., Singh, V., Verma, A., Yochum, G., Koltun, W., Nighot, M., Ma, T., Nighot, P., 2022. AP2M1 mediates autophagy-induced CLDN2 (claudin 2) degradation through endocytosis and interaction with LC3 and reduces intestinal epithelial tight junction permeability. Autophagy, 18, 2086-2103.

      16. Gautam, A., Kaphle, K., Shrestha, B., Phuyal, S., 2020. Susceptibility to SARS, MERS, and COVID-19 from animal health perspective. Open Vet J, 10, 164-177.

      17. Harrison, A.G., Lin, T., Wang, P., 2020. Mechanisms of SARS-CoV-2 Transmission and Pathogenesis. Trends Immunol, 41, 1100-1115.

      18. Helbig, I., Lopez-Hernandez, T., Shor, O., Galer, P., Ganesan, S., Pendziwiat, M., Rademacher, A., Ellis, C.A., Humpfer, N., Schwarz, N., Seiffert, S., Peeden, J., Shen, J., Sterbova, K., Hammer, T.B., Moeller, R.S., Shinde, D.N., Tang, S., Smith, L., Poduri, A., Krause, R., Benninger, F., Helbig, K.L., Haucke, V., Weber, Y.G.; EuroEPINOMICS-RES Consortium; GRIN Consortium., 2019. A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. Am J Hum Genet, 104, 1060-1072.

      19. Henne, W.M., Boucrot, E., Meinecke, M., Evergren, E., Vallis, Y., Mittal, R., Mcmahon, H.T., 2010. FCHo proteins are nucleators of clathrin-mediated endocytosis. Science, 328, 1281-1284.

      20. Hussain, K.M., Leong, K.L., Ng, M.M., Chu, J.J., 2011. The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71. J Biol Chem, 286, 309-321.

      21. Kesheh, M.M., Hosseini, P., Soltani, S., Zandi, M., 2022. An overview on the seven pathogenic human coronaviruses. Rev Med Virol, 32, e2282.

      22. Koehler, M., Delguste, M., Sieben, C., Gillet, L., Alsteens, D., 2020. Initial Step of Virus Entry: Virion Binding to Cell-Surface Glycans. Annu Rev Virol, 7, 143-165.

      23. Kong, N., Shan, T., Wang, H., Jiao, Y., Zuo, Y., Li, L., Tong, W., Yu, L., Jiang, Y., Zhou, Y., Li, G., Gao, F., Yu, H., Zheng, H., Tong, G., 2020. BST2 suppresses porcine epidemic diarrhea virus replication by targeting and degrading virus nucleocapsid protein with selective autophagy. Autophagy, 16, 1737-1752.

      24. Lee, W., Kim, H.Y., Choi, Y.J., Jung, S.H., Nam, Y.A., Zhang, Y., Yun, S.H., Chang, T.S., Lee, B.H., 2022. SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation. Theranostics, 12, 2351-2369.

      25. Liao, Z., Si, T., Kai, J.J., Fan, J., 2024. Mechanism of Membrane Curvature Induced by SNX1: Insights from Molecular Dynamics Simulations. J Phys Chem B, 128, 2144-2153.

      26. Liu, Q., Bautista-Gomez, J., Higgins, D.A., Yu, J., Xiong, Y., 2021. Dysregulation of the AP2M1 phosphorylation cycle by LRRK2 impairs endocytosis and leads to dopaminergic neurodegeneration. Sci Signal, 14, eabg3555.

      27. Lopez-Munoz, A.D., Santos, J.J.S., Yewdell, J.W., 2023. Cell Surface Nucleocapsid Protein Expression: A Betacoronavirus Immunomodulatory Strategy. bioRxiv, 10.1101/2023.02.24.529952.

      28. Lou, J., Li, X., Huang, W., Liang, J., Zheng, M., Xu, T., Lyu, J., Li, D., Xu, Q., Jin, X., Fu, G., Wang, D., Lu, L., 2017. SNX10 promotes phagosome maturation in macrophages and protects mice against Listeria monocytogenes infection. Oncotarget, 8, 53935-53947.

      29. Lou, Y., Zhang, J., Wang, G., Fang, W., Wang, S., Abubakar, Y.S., Zhou, J., Wang, Z., Zheng, W., 2021. Genome-Wide Characterization of PX Domain-Containing Proteins Involved in Membrane Trafficking-Dependent Growth and Pathogenicity of Fusarium graminearum. mBio, 12, e0232421.

      30. Lu, Y., He, P., Zhang, Y., Ren, Y., Zhang, L., 2022. The emerging roles of retromer and sorting nexins in the life cycle of viruses. Virol Sin, 37, 321-330.

      31. Malik, Y.A., 2020. Properties of Coronavirus and SARS-CoV-2. Malays J Pathol, 42, 3-11.

      32. Malone, B., Urakova, N., Snijder, E.J., Campbell, E.A., 2022. Structures and functions of coronavirus replication-transcription complexes and their relevance for SARS-CoV-2 drug design. Nat Rev Mol Cell Biol, 23, 21-39.

      33. Mettlen, M., Chen, P.H., Srinivasan, S., Danuser, G., Schmid, S.L., 2018. Regulation of Clathrin-Mediated Endocytosis. Annu Rev Biochem, 87, 871-896.

      34. Miller, K., Mcgrath, M.E., Hu, Z., Ariannejad, S., Weston, S., Frieman, M., Jackson, W.T., 2020. Coronavirus interactions with the cellular autophagy machinery. Autophagy, 16, 2131-2139.

      35. Muller, T.G., Zila, V., Peters, K., Schifferdecker, S., Stanic, M., Lucic, B., Laketa, V., Lusic, M., Muller, B., Krausslich, H.G., 2021. HIV-1 uncoating by release of viral cDNA from capsid-like structures in the nucleus of infected cells. Elife, 10, e64776.

      36. Norris, A., Tammineni, P., Wang, S., Gerdes, J., Murr, A., Kwan, K.Y., Cai, Q., Grant, B.D., 2017. SNX-1 and RME-8 oppose the assembly of HGRS-1/ESCRT-0 degradative microdomains on endosomes. Proc Natl Acad Sci U S A, 114, E307-E316.

      37. Peng, Y., Du, N., Lei, Y., Dorje, S., Qi, J., Luo, T., Gao, G.F., Song, H., 2020. Structures of the SARS-CoV-2 nucleocapsid and their perspectives for drug design. Embo J, 39, e105938.

      38. Schmidt, O., Weyer, Y., Fink, M.J., Muller, M., Weys, S., Bindreither, M., Teis, D., 2017. Regulation of Rab5 isoforms by transcriptional and post-transcriptional mechanisms in yeast. FEBS Lett, 591, 2803-2815.

      39. Shang, J., Wan, Y., Luo, C., Ye, G., Geng, Q., Auerbach, A., Li, F., 2020. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A, 117, 11727-11734.

      40. Tan, Y.J., Lim, S.G., Hong, W., 2006. Understanding the accessory viral proteins unique to the severe acute respiratory syndrome (SARS) coronavirus. Antiviral Res, 72, 78-88.

      41. Tian, Y., Kang, Q., Shi, X., Wang, Y., Zhang, N., Ye, H., Xu, Q., Xu, T., Zhang, R., 2021. SNX-3 mediates retromer-independent tubular endosomal recycling by opposing EEA-1-facilitated trafficking. PLoS Genet, 17, e1009607.

      42. Tongmuang, N., Yasamut, U., Noisakran, S., Sreekanth, G.P., Yenchitsomanus, P.T., Limjindaporn, T., 2020. Suppression of μ1 subunit of the adaptor protein complex 2 reduces dengue virus release. Virus Genes, 56, 27-36.

      43. Tscherne, D.M., Jones, C.T., Evans, M.J., Lindenbach, B.D., Mckeating, J.A., Rice, C.M., 2006. Time- and temperature-dependent activation of hepatitis C virus for low-pH-triggered entry. J Virol, 80, 1734-1741.

      44. Van Weering, J.R., Verkade, P., Cullen, P.J., 2010. SNX-BAR proteins in phosphoinositide-mediated, tubular-based endosomal sorting. Semin Cell Dev Biol, 21, 371-380.

      45. Vijgen, L., Keyaerts, E., Moes, E., Thoelen, I., Wollants, E., Lemey, P., Vandamme, A.M., Van Ranst, M., 2005. Complete genomic sequence of human coronavirus OC43: molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event. J Virol, 79, 1595-1604.

      46. Wang, C., Hesketh, E.L., Shamorkina, T.M., Li, W., Franken, P.J., Drabek, D., Van Haperen, R., Townend, S., Van Kuppeveld, F.J.M., Grosveld, F., Ranson, N.A., Snijder, J., De Groot, R.J., Hurdiss, D.L., Bosch, B.J., 2022. Antigenic structure of the human coronavirus OC43 spike reveals exposed and occluded neutralizing epitopes. Nat Commun, 13, 2921.

      47. Wang, G., Jiang, L., Wang, J., Zhang, J., Kong, F., Li, Q., Yan, Y., Huang, S., Zhao, Y., Liang, L., Li, J., Sun, N., Hu, Y., Shi, W., Deng, G., Chen, P., Liu, L., Zeng, X., Tian, G., Bu, Z., Chen, H., Li, C., 2020a. The G Protein-Coupled Receptor FFAR2 Promotes Internalization during Influenza A Virus Entry. J Virol, 94, e01707-e01719.

      48. Wang, P.G., Tang, D.J., Hua, Z., Wang, Z., An, J., 2020b. Sunitinib reduces the infection of SARS-CoV, MERS-CoV and SARS-CoV-2 partially by inhibiting AP2M1 phosphorylation. Cell Discov, 6, 71.

      49. Wang, X., Ni, J., You, Y., Feng, G., Zhang, S., Bao, W., Hou, H., Li, H., Liu, L., Zheng, M., Wang, Y., Zhou, H., Shen, W., Shen, X., 2021. SNX10-mediated LPS sensing causes intestinal barrier dysfunction via a caspase-5-dependent signaling cascade. Embo j, 40, e108080.

      50. Weeratunga, S., Paul, B., Collins, B.M., 2020. Recognising the signals for endosomal trafficking. Curr Opin Cell Biol, 65, 17-27.

      51. Wu, D., Wang, Y., Xu, J., Wang, D., Zhang, J., Meng, L., Hu, Y., Wang, P., Lin, J., Zhou, S., 2024. SNX10 promoted liver IR injury by facilitating macrophage M1 polarization via NLRP3 inflammasome activation. Mol Immunol, 166, 79-86.

      52. Yamauchi, Y., 2020. Influenza A virus uncoating. Adv Virus Res, 106, 1-38.

      53. You, Y., Li, W.Z., Zhang, S., Hu, B., Li, Y.X., Li, H.D., Tang, H.H., Li, Q.W., Guan, Y.Y., Liu, L.X., Bao, W.L., Shen, X., 2018. SNX10 mediates alcohol-induced liver injury and steatosis by regulating the activation of chaperone-mediated autophagy. J Hepatol, 69, 129-141.

      54. You, Y., Zhou, C., Li, D., Cao, Z.L., Shen, W., Li, W.Z., Zhang, S., Hu, B., Shen, X., 2016. Sorting nexin 10 acting as a novel regulator of macrophage polarization mediates inflammatory response in experimental mouse colitis. Sci Rep, 6, 20630.

      55. Yousefi, M., Lee, W.S., Yan, B., Cui, L., Yong, C.L., Yap, X., Tay, K.S.L., Qiao, W., Tan, D., Nurazmi, N.I., Linster, M., Smith, G.J.D., Lee, Y.H., Carette, J.E., Ooi, E.E., Chan, K.R., Ooi, Y.S., 2022. TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating dengue virus infection. PLoS Pathog, 18, e1010763.

      56. Yuan, S., Chu, H., Huang, J., Zhao, X., Ye, Z.W., Lai, P.M., Wen, L., Cai, J.P., Mo, Y., Cao, J., Liang, R., Poon, V.K., Sze, K.H., Zhou, J., To, K.K., Chen, Z., Chen, H., Jin, D.Y., Chan, J.F., Yuen, K.Y., 2020. Viruses harness YxxOE motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target. Sci Adv, 6, eaba7910.

      57. Zhang, Y., Srivastava, V., Zhang, B., 2023. Mammalian cargo receptors for endoplasmic reticulum-to-Golgi transport: mechanisms and interactions. Biochem Soc Trans, 51, 971-981.

    • 加载中

    Figures(1)

    PDF

    Article Metrics

    Article views(621) PDF downloads(17) Cited by()

    Related
    Proportional views

      SNX10 enhances HCoV-OC43 infection by facilitating viral entry and inhibiting virus-triggered autophagy

        Corresponding author: Shuwen Liu, liusw@smu.edu.cn
      • a. Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China;
      • b. Department of Pharmacy, Jinan University Affiliated Guangdong Second Provincial General Hospital, Guangzhou, 510317, China;
      • c. MOE Key Laboratory of Infectious Diseases Research in South China, MOE Innovation Center for Medical Basic Research on Inflammation and Immune Related Diseases, Southern Medical University, Guangzhou, 510515, China;
      • d. NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Department of Pharmacy, Pingshan Hospital, Southern Medical University, Shenzhen, 518100, China;
      • e. State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou, 510515, China
      • Received Date: 22 March 2025
      • Accepted Date: 07 July 2025

      Abstract: The ongoing coronavirus epidemic, including the novel coronavirus (SARS-CoV-2), continues to pose a significant threat to global public health. Host targets address multiple stages of the viral life cycle and provide diverse opportunities for therapeutic interventions. This study identified sorting nexin 10 (SNX10) as a facilitator of replication of human coronavirus OC43 (HCoV-OC43), underscoring its potential as a novel antiviral target. The knockout of SNX10 significantly suppressed HCoV-OC43 replication both in vivo and in vitro. Immunoprecipitation-mass spectrometry (‌IP-MS) analysis identified the adaptor protein complex 2 subunit μ1 (AP2M1) as a direct interactor of SNX10. Specifically, SNX10 facilitates phosphorylation of the AP2M1, thereby enhancing clathrin-mediated viral endocytosis. Furthermore, subsequent binding and internalization assays revealed that SNX10 knockout significantly inhibits viral entry into host cells. Conversely, the reconstitution of SNX10 fully restored viral entry, thereby confirming the critical and indispensable role of SNX10 in pathogen internalization. Simultaneously, SNX10 was identified as a key factor that promotes endosomal acidification by modulating pH levels, which in turn facilitated the release of the viral genome. Notably, the ablation of SNX10 was found to trigger autophagy activation during infection, thereby maintaining intracellular homeostasis. Additionally, it exerted autonomous antiviral effects through lysosomal degradation pathways. Collectively, these findings demonstrate SNX10 serves as a pivotal regulator of the viral life cycle and underscore its therapeutic potential as a multi-faceted antiviral candidate target capable of simultaneously inhibiting viral internalization, viral genomic release, and host-pathogen equilibrium.

        HTML

      Figure (1)  Reference (57) Relative (20)

      目录

      This journal is a member of, and subscribes to the principles of, the Committee on Publication Ethics (COPE)

      鄂ICP备05001977号

         

      鄂公网安备 42010602003674号

      Copyright © 2019 Virologica Sinica. All rights reserved

      /

      DownLoad:  Full-Size Img  PowerPoint
      Return
      Return