Serine incorporator 5 (SERINC5) restricts the infectivity of various enveloped viruses, including HIV-1 and severe acute respiratory syndrome coronavirus 2. However, these pandemic viral pathogens have evolved mechanisms to counteract this restriction. Here, we examined the impact of all five human SERINC family members on the seasonal human coronaviruses (hCoVs) 229E and OC43, which account for up to 15% of global mild respiratory infections and can cause severe disease in vulnerable individuals. Our data show that both exogenous and endogenous SERINC1, SERINC3, and SERINC5 significantly reduce OC43 infectivity in human lung and liver cells but have little, if any, effect on 229E. Functional analyses revealed that both the 130-amino-acid ORF4a protein encoded by most laboratory 229E strains and the full-length 219 amino acid ORF4 protein encoded by clinical 229E isolates antagonize SERINC5 by promoting its relocalization to lysosomes and subsequent degradation. Finally, we show that endogenous SERINC5 expression in primary human lung cells inhibits infection by ORF4-deficient but not wild-type hCoV-229E. In conclusion, several SERINC proteins restrict hCoV-OC43, whereas hCoV-229E efficiently counteracts SERINC-mediated restriction by its ORF4/4a accessory proteins to ensure efficient production of fully infectious viral particles.
| [1] |
A. M. Alluwaimi, I. H. Alshubaith, A. M. Al-Ali, and S. Abohelaika, “The Coronaviruses of Animals and Birds: Their Zoonosis, Vaccines, and Models for SARS-CoV and SARS-CoV2,” Frontiers in Veterinary Science 7, no. 582287 (2020): 582287.
|
| [2] |
A. S. Monto and B. J. Cowling, Coronaviruses PJSM “Viral Infections of Humans,” (2014): 199–223, Published online February.
|
| [3] |
Coronaviridae Study Group of the International Committee on Taxonomy of V. The Species Severe Acute respiratory Syndrome-Related Coronavirus: Classifying 2019-nCoV and Naming It SARS-CoV-2. Nature Microbiology 2020; 5(4): 536–544.
|
| [4] |
A. Bermingham, M. A. Chand, C. S. Brown, et al., “Severe respiratory Illness Caused by a Novel Coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012,” Euro Surveillance 17, no. 40 (2012): 20290.
|
| [5] |
T. G. Ksiazek, D. Erdman, C. S. Goldsmith, et al., “A Novel Coronavirus Associated With Severe Acute respiratory Syndrome,” New England Journal of Medicine 348, no. 20 (2003): 1953–1966.
|
| [6] |
V. M. Corman, D. Muth, D. Niemeyer, and C. Drosten, “Hosts and Sources of Endemic Human Coronaviruses,” Advances in Virus Research 100 (2018): 163–188.
|
| [7] |
J. Cui, F. Li, and Z. L. Shi, Origin and Evolution of Pathogenic Coronaviruses (Nature Publishing Group, 2019).
|
| [8] |
A. M. Fendrick, A. S. Monto, B. Nightengale, and M. Sarnes, “The Economic Burden of Non-Influenza-Related Viral respiratory Tract Infection in the United States,” Archives of Internal Medicine 163, no. 4 (2003): 487–494.
|
| [9] |
A. Veiga, L. G. Martins, I. Riediger, A. Mazetto, M. D. C. Debur, and T. S. Gregianini, “More Than Just a Common Cold: Endemic Coronaviruses OC43, HKU1, NL63, and 229E Associated With Severe Acute respiratory Infection and Fatality Cases Among Healthy Adults,” Journal of Medical Virology 93, no. 2 (2021): 1002–1007.
|
| [10] |
B. Escudero-Perez, A. Lalande, C. Mathieu, and P. Lawrence, “Host-Pathogen Interactions Influencing Zoonotic Spillover Potential and Transmission in Humans,” Viruses 15, no. 3 (2023): 599.
|
| [11] |
A. Gaba, B. Flath, and L. Chelico, “Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses,” Viruses 13, no. 6 (2021): 1084.
|
| [12] |
P. P. Petric, M. Schwemmle, and L. Graf, “Anti-Influenza A Virus Restriction Factors That Shape the human Species Barrier and Virus Evolution,” Plos Pathogens 19, no. 7 (2023): e1011450.
|
| [13] |
D. Sauter and F. Kirchhoff, “Key Viral Adaptations Preceding the AIDS Pandemic,” Cell Host & Microbe 25, no. 1 (2019): 27–38.
|
| [14] |
N. Chen, J. Jin, and B. Zhang, “Viral Strategies to Antagonize the Host Antiviral Innate Immunity: An Indispensable Research Direction for Emerging Virus-Host Interactions,” Emerging Microbes & Infections 13, no. 1 (2024): 2341144.
|
| [15] |
S. F. Kluge, D. Sauter, and F. Kirchhoff, “SnapShot: Antiviral Restriction Factors,” Cell 163, no. 3 (2015): 774-774 e1.
|
| [16] |
D. Kmiec and F. Kirchhoff, “Antiviral Factors and Their Counteraction by HIV-1: Many Uncovered and More to be Discovered,” Journal of Molecular Cell Biology 16, no. 2 (2024): mjae005.
|
| [17] |
H. Hoenigsperger, R. Sivarajan, and K. M. Sparrer, “Differences and Similarities Between Innate Immune Evasion Strategies of human Coronaviruses,” Current Opinion in Microbiology 79, no. 102466 (2024): 102466.
|
| [18] |
A. Rosa, A. Chande, S. Ziglio, et al., “HIV-1 Nef Promotes Infection by Excluding SERINC5 From Virion Incorporation,” Nature 526, no. 7572 (2015): 212–217.
|
| [19] |
U. Timilsina, S. Umthong, E. B. Ivey, B. Waxman, and S. Stavrou, “SARS-CoV-2 ORF7a Potently Inhibits the Antiviral Effect of the Host Factor SERINC5,” Nature Communications 13, no. 1 (2022): 2935.
|
| [20] |
Y. Usami, Y. Wu, and H. G. Gottlinger, “SERINC3 and SERINC5 Restrict HIV-1 Infectivity and Are Counteracted by Nef,” Nature 526, no. 7572 (2015): 218–223.
|
| [21] |
J. Kirschman, M. Marin, Y. C. Chen, et al., “SERINC5 Restricts HIV-1 Infectivity by Promoting Conformational Changes and Accelerating Functional Inactivation of Env,” Viruses 14, no. 7 (2022): 1388.
|
| [22] |
C. Sood, M. Marin, A. Chande, M. Pizzato, and G. B. Melikyan, “SERINC5 protein Inhibits HIV-1 Fusion Pore Formation by Promoting Functional Inactivation of Envelope Glycoproteins,” Journal of Biological Chemistry 292, no. 14 (2017): 6014–6026.
|
| [23] |
B. Trautz, H. Wiedemann, C. Luchtenborg, et al., “The Host-Cell Restriction Factor SERINC5 Restricts HIV-1 Infectivity Without Altering the Lipid Composition and Organization of Viral Particles,” Journal of Biological Chemistry 292, no. 33 (2017): 13702–13713.
|
| [24] |
B. Trautz, V. Pierini, R. Wombacher, et al., “The Antagonism of HIV-1 Nef to SERINC5 Particle Infectivity Restriction Involves the Counteraction of Virion-Associated Pools of the Restriction Factor,” Journal of Virology 90, no. 23 (2016): 10915–10927.
|
| [25] |
S. A. Leonhardt, M. D. Purdy, J. R. Grover, et al., “Antiviral HIV-1 SERINC Restriction Factors Disrupt Virus Membrane Asymmetry,” Nature Communications 14, no. 1 (2023): 4368.
|
| [26] |
A. Featherstone and C. Aiken, “SERINC5 Inhibits HIV-1 Infectivity by Altering the Conformation of gp120 on HIV-1 Particles,” Journal of Virology 94, no. 20 (2020): e00594–20.
|
| [27] |
S. Sid Ahmed, K. Bajak, and O. T. Fackler, “Beyond Impairment of Virion Infectivity: New Activities of the Anti-HIV Host Cell Factor SERINC5,” Viruses 16, no. 2 (2024): 284.
|
| [28] |
S. Meseguer, M. P. Rubio, B. Lainez, et al., “SARS-CoV-2-Encoded Small RNAs Are Able to Repress the Host Expression of SERINC5 to Facilitate Viral Replication,” Frontiers in Microbiology 14 (2023): 1066493.
|
| [29] |
N. Decaro and A. Lorusso, “Novel human Coronavirus (SARS-CoV-2): A Lesson From Animal Coronaviruses,” Veterinary Microbiology 244, no. 108693 (2020): 108693.
|
| [30] |
K. Munir, S. Ashraf, I. Munir, et al., “Zoonotic and Reverse Zoonotic Events of SARS-CoV-2 and Their Impact on Global Health,” Emerging Microbes & Infections 9, no. 1 (2020): 2222–2235.
|
| [31] |
N. Nova, “Cross-Species Transmission of Coronaviruses in Humans and Domestic Mammals, What Are the Ecological Mechanisms Driving Transmission, Spillover, and Disease Emergence?,” Frontiers in Public Health 9, no. 717941 (2021): 717941.
|
| [32] |
D. Forni, R. Cagliani, F. Arrigoni, et al., “Adaptation of the Endemic Coronaviruses HCoV-OC43 and HCoV-229E to the human Host,” Virus Evolution 7, no. 2 (2021): veab061.
|
| [33] |
R. R. Ghai, A. Carpenter, A. Y. Liew, et al., “Animal Reservoirs and Hosts for Emerging Alphacoronaviruses and Betacoronaviruses,” Emerging Infectious Diseases 27, no. 4 (2021): 1015–1022.
|
| [34] |
Q. Li, T. Shah, B. Wang, et al., “Cross-Species Transmission, Evolution and Zoonotic Potential of Coronaviruses,” Frontiers in Cellular and Infection Microbiology 12 (2022): 1081370.
|
| [35] |
D. Forni, R. Cagliani, U. Pozzoli, et al., “Dating the Emergence of Human Endemic Coronaviruses,” Viruses 14, no. 5 (2022): 1095.
|
| [36] |
C. Firrito, C. Bertelli, T. Vanzo, A. Chande, and M. Pizzato, “SERINC5 as a New Restriction Factor for Human Immunodeficiency Virus and Murine Leukemia Virus,” Annual Review of Virology 5, no. 1 (2018): 323–340.
|
| [37] |
X. Qiu, I. E. Eke, S. F. Johnson, C. Ding, and Y. H. Zheng, “Proteasomal Degradation of human SERINC4: A Potent Host Anti-HIV-1 Factor That Is Antagonized by nef,” Current Research in Virological Science 1 (2020): 100002.
|
| [38] |
G. J. Mahler, M. L. Shuler, and R. P. Glahn, “Characterization of Caco-2 and HT29-MTX Cocultures in an in Vitro Digestion/Cell Culture Model Used to Predict Iron Bioavailability,” Journal of Nutritional Biochemistry 20, no. 7 (2009): 494–502.
|
| [39] |
C. W. Chang, K. M. Parsi, M. Somasundaran, et al., “A Newly Engineered A549 Cell Line Expressing ACE2 and TMPRSS2 Is Highly Permissive to SARS-CoV-2, Including the Delta and Omicron Variants,” Viruses 14, no. 7 (2022): 1369.
|
| [40] |
J. Fogh, J. M. Fogh, and T. Orfeo, “One Hundred and Twenty-Seven Cultured Human Tumor Cell Lines Producing Tumors in Nude Mice,” JNCI: Journal of the National Cancer Institute 59, no. 1 (1977): 221–226.
|
| [41] |
P. de Sousa-Pereira, J. Abrantes, S. Bauernfried, et al., “The Antiviral Activity of Rodent and Lagomorph SERINC3 and SERINC5 Is Counteracted by Known Viral Antagonists,” Journal of General Virology 100, no. 2 (2019): 278–288.
|
| [42] |
A. Heigele, D. Kmiec, K. Regensburger, et al., “The Potency of Nef-Mediated SERINC5 Antagonism Correlates With the Prevalence of Primate Lentiviruses in the Wild,” Cell Host & Microbe 20, no. 3 (2016): 381–391.
|
| [43] |
B. Murrell, T. Vollbrecht, J. Guatelli, and J. O. Wertheim, “The Evolutionary Histories of Antiretroviral Proteins SERINC3 and SERINC5 Do Not Support an Evolutionary Arms Race in Primates,” Journal of Virology 90, no. 18 (2016): 8085–8089.
|
| [44] |
L. Vijgen, E. Keyaerts, E. Moes, et al., “Complete Genomic Sequence of human Coronavirus OC43: Molecular Clock Analysis Suggests a Relatively Recent Zoonotic Coronavirus Transmission Event,” Journal of Virology 79, no. 3 (2005): 1595–1604.
|
| [45] |
V. E. Pye, A. Rosa, C. Bertelli, et al., “A Bipartite Structural Organization Defines the SERINC family of HIV-1 Restriction Factors,” Nature Structural & Molecular Biology 27, no. 1 (2020): 78–83.
|
| [46] |
Z. Wen, Y. Zhang, Z. Lin, K. Shi, and Y. Jiu, “Cytoskeleton-a Crucial Key in Host Cell for Coronavirus Infection,” Journal of Molecular Cell Biology 12, no. 12 (2020): 968–979.
|
| [47] |
P. S. Masters, “The Molecular Biology of Coronaviruses,” Advances in Virus Research 66 (2006): 193–292.
|
| [48] |
S. C. Devarkar, M. Vetick, S. Balaji, et al., “Structural Basis for Translation Inhibition by MERS-CoV Nsp1 Reveals a Conserved Mechanism for Betacoronaviruses,” Cell Reports 42, no. 10 (2023): 113156.
|
| [49] |
M. Thoms, R. Buschauer, M. Ameismeier, et al., “Structural Basis for Translational Shutdown and Immune Evasion by the Nsp1 Protein of SARS-CoV-2,” Science 369, no. 6508 (2020): 1249–1255.
|
| [50] |
R. Zhang, K. Wang, W. Lv, et al., “The ORF4a Protein of human Coronavirus 229E Functions as a Viroporin That Regulates Viral Production,” Biochimica Et Biophysica Acta 1838, no. 4 (2014): 1088–1095.
|
| [51] |
M. Ambrozek-Latecka, P. Kozlowski, G. Hoser, et al., “SARS-CoV-2 and Its ORF3a, E and M Viroporins Activate Inflammasome in human Macrophages and Induce of IL-1alpha in Pulmonary Epithelial and Endothelial Cells,” Cell Death Discovery 10, no. 1 (2024): 191.
|
| [52] |
R. Zhang, K. Wang, X. Ping, et al., “The ns12.9 Accessory Protein of Human Coronavirus OC43 Is a Viroporin Involved in Virion Morphogenesis and Pathogenesis,” Journal of Virology 89, no. 22 (2015): 11383–11395.
|
| [53] |
A. C. Brant, W. Tian, V. Majerciak, W. Yang, and Z. M. Zheng, “SARS-CoV-2: From Its Discovery to Genome Structure, Transcription, and Replication,” Cell Bioscience 11, no. 1 (2021): 136.
|
| [54] |
L. Koepke, B. Winter, A. Grenzner, et al., “An Improved Method for High-Throughput Quantification of Autophagy in Mammalian Cells,” Scientific Reports 10, no. 1 (2020): 12241.
|
| [55] |
R. Dijkman, M. F. Jebbink, B. Wilbrink, et al., “Human Coronavirus 229E Encodes a Single ORF4 Protein Between the Spike and the Envelope Genes,” Virology Journal 3, no. 1 (2006): 106.
|
| [56] |
V. Thiel, J. Herold, B. Schelle, and S. G. Siddell, “Viral Replicase Gene Products Suffice for Coronavirus Discontinuous Transcription,” Journal of Virology 75, no. 14 (2001): 6676–6681.
|
| [57] |
L. Cervantes-Barragan, R. Zust, R. Maier, et al., “Dendritic Cell-Specific Antigen Delivery by Coronavirus Vaccine Vectors Induces Long-Lasting Protective Antiviral and Antitumor Immunity,” MBio 1, no. 4 (2010): e00171–10.
|
| [58] |
K. Hardy, M. Lutz, and T. Takimoto, “Human Coronavirus NL63 nsp1 Induces Degradation of RNA Polymerase II to Inhibit Host Protein Synthesis,” Plos Pathogens 20, no. 6 (2024): e1012329.
|
| [59] |
J. Shi, R. Xiong, T. Zhou, et al., “HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome/Lysosome System,” Journal of Virology 92, no. 11 (2018): e00196–18.
|
| [60] |
D. Kmiec, B. Akbil, S. Ananth, et al., “SIVcol Nef Counteracts SERINC5 by Promoting Its Proteasomal Degradation but Does Not Efficiently Enhance HIV-1 Replication in human CD4+ T Cells and Lymphoid Tissue,” Plos Pathogens 14, no. 8 (2018): e1007269.
|
| [61] |
S. Beitari, S. Ding, Q. Pan, A. Finzi, and C. Liang, “Effect of HIV-1 Env on SERINC5 Antagonism,” Journal of Virology 91, no. 4 (2017): e02214–e02216.
|
| [62] |
T. Haider, X. Snetkov, and C. Jolly, “HIV Envelope Tail Truncation Confers Resistance to SERINC5 Restriction,” Proceedings of the National Academy of Sciences of the United States of America 118, no. 21 (2021): e2101450118.
|
| [63] |
W. I. Choi, I. B. Kim, S. J. Park, E. H. Ha, and C. W. Lee, “Comparison of the Clinical Characteristics and Mortality of Adults Infected With human Coronaviruses 229E and OC43,” Scientific Reports 11, no. 1 (2021): 4499.
|
| [64] |
I. Saib, S. Aleisa, H. Ardah, et al., “Non-SARS Non-MERS Human Coronaviruses: Clinical Characteristics and Outcome,” Pathogens 10, no. 12 (2021): 1549.
|
| [65] |
E. E. Walsh, J. H. Shin, and A. R. Falsey, “Clinical Impact of human Coronaviruses 229E and OC43 Infection in Diverse Adult Populations,” Journal of Infectious Diseases 208, no. 10 (2013): 1634–1642.
|
| [66] |
Z. W. Ye, S. Yuan, K. S. Yuen, S. Y. Fung, C. P. Chan, and D. Y. Jin, “Zoonotic Origins of human Coronaviruses,” International Journal of Biological Sciences 16, no. 10 (2020): 1686–1697.
|
| [67] |
M. Sironi, R. Cagliani, D. Forni, and M. Clerici, “Evolutionary Insights Into Host-Pathogen Interactions From Mammalian Sequence Data,” Nature Reviews Genetics 16, no. 4 (2015): 224–236.
|
| [68] |
Y. Shi, S. Simpson, S. K. Ahmed, et al., “The Antiviral Factor SERINC5 Impairs the Expression of Non-Self-DNA,” Viruses 15, no. 9 (2023): 1961.
|
| [69] |
P. Ramdas, V. Bhardwaj, A. Singh, N. Vijay, and A. Chande, “Coelacanth SERINC2 Inhibits HIV-1 Infectivity and Is Counteracted by Envelope Glycoprotein From Foamy Virus,” Journal of Virology 95, no. 13 (2021): e0022921.
|
| [70] |
B. Weller, C.-W. Lin, O. Pogoutse, et al., “A resource of human coronavirus protein-Coding Sequences in a Flexible, Multipurpose Gateway Entry Clone Collection,” G3 (Bethesda) 13, no. 7 (2023): jkad105.
|
| [71] |
J. Lawrenz, Q. Xie, F. Zech, et al., “Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination Boosts Neutralizing Activity against Seasonal Human Coronaviruses,” Clinical Infectious Diseases 75, no. 1 (2022): e653–e661.
|
| [72] |
L. J. Reed and H. Muench, “A Simple Method of Estimating Fifty per Cent Endpoints12,” American Journal of Epidemiology 27, no. 3 (1938): 493–497.
|
| [73] |
S. Klute, R. Nchioua, A. Cordsmeier, et al., “Mutation T9I in Envelope confers autophagy resistance to SARS-CoV-2 Omicron,” iScience 28, no. 7 (2025): 112974.
|
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