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LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2.
J Virol. 2020 08 31; 94(18)JV

Abstract

C3A is a subclone of the human hepatoblastoma HepG2 cell line with strong contact inhibition of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into C3A cells. In an effort to search for the host cellular protein(s) mediating the differential susceptibility of the two cell lines to HCoV-OC43 infection, we found that ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2), gamma-interferon-inducible lysosome/endosome-localized thiolreductase (GILT), and lymphocyte antigen 6 family member E (LY6E), the three cellular proteins identified to function in interference with virus entry, were expressed at significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-O43. While overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry mediated by the envelope spike proteins of other human coronaviruses, including the currently pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or amphotericin treatment significantly neutralized the IFN-inducible transmembrane 3 (IFITM3) restriction of human coronavirus (CoV) entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis via a mechanism distinct from other factors that modulate CoV entry.IMPORTANCE Virus entry into host cells is one of the key determinants of host range and cell tropism and is subjected to the control of host innate and adaptive immune responses. In the last decade, several interferon-inducible cellular proteins, including IFITMs, GILT, ADAP2, 25CH, and LY6E, had been identified to modulate the infectious entry of a variety of viruses. Particularly, LY6E was recently identified as a host factor that facilitates the entry of several human-pathogenic viruses, including human immunodeficiency virus, influenza A virus, and yellow fever virus. Identification of LY6E as a potent restriction factor of coronaviruses expands the biological function of LY6E and sheds new light on the immunopathogenesis of human coronavirus infection.

Authors+Show Affiliations

Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China zhaoxuesen@ccmu.edu.cn ju-tao.guo@bblumberg.org. Beijing Key Laboratory of Emerging Infectious Disease, Beijing, China. Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA.Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China. Beijing Key Laboratory of Emerging Infectious Disease, Beijing, China.Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China. Beijing Key Laboratory of Emerging Infectious Disease, Beijing, China.Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China. Beijing Key Laboratory of Emerging Infectious Disease, Beijing, China.Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China. Beijing Key Laboratory of Emerging Infectious Disease, Beijing, China.Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China. Beijing Key Laboratory of Emerging Infectious Disease, Beijing, China.Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA.Institute of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China. Beijing Key Laboratory of Emerging Infectious Disease, Beijing, China.Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, Pennsylvania, USA zhaoxuesen@ccmu.edu.cn ju-tao.guo@bblumberg.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32641482

Citation

Zhao, Xuesen, et al. "LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2." Journal of Virology, vol. 94, no. 18, 2020.
Zhao X, Zheng S, Chen D, et al. LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2. J Virol. 2020;94(18).
Zhao, X., Zheng, S., Chen, D., Zheng, M., Li, X., Li, G., Lin, H., Chang, J., Zeng, H., & Guo, J. T. (2020). LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2. Journal of Virology, 94(18). https://doi.org/10.1128/JVI.00562-20
Zhao X, et al. LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2. J Virol. 2020 08 31;94(18) PubMed PMID: 32641482.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - LY6E Restricts Entry of Human Coronaviruses, Including Currently Pandemic SARS-CoV-2. AU - Zhao,Xuesen, AU - Zheng,Shuangli, AU - Chen,Danying, AU - Zheng,Mei, AU - Li,Xinglin, AU - Li,Guoli, AU - Lin,Hanxin, AU - Chang,Jinhong, AU - Zeng,Hui, AU - Guo,Ju-Tao, Y1 - 2020/08/31/ PY - 2020/03/30/received PY - 2020/07/05/accepted PY - 2020/7/10/pubmed PY - 2020/9/15/medline PY - 2020/7/10/entrez KW - LY6E KW - SARS-CoV-2 KW - human coronavirus KW - viral entry JF - Journal of virology JO - J. Virol. VL - 94 IS - 18 N2 - C3A is a subclone of the human hepatoblastoma HepG2 cell line with strong contact inhibition of growth. We fortuitously found that C3A was more susceptible to human coronavirus HCoV-OC43 infection than HepG2, which was attributed to the increased efficiency of virus entry into C3A cells. In an effort to search for the host cellular protein(s) mediating the differential susceptibility of the two cell lines to HCoV-OC43 infection, we found that ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2), gamma-interferon-inducible lysosome/endosome-localized thiolreductase (GILT), and lymphocyte antigen 6 family member E (LY6E), the three cellular proteins identified to function in interference with virus entry, were expressed at significantly higher levels in HepG2 cells. Functional analyses revealed that ectopic expression of LY6E, but not GILT or ADAP2, in HEK 293 cells inhibited the entry of HCoV-O43. While overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-OC43, knockdown of LY6E expression in HepG2 significantly increased its susceptibility to HCoV-OC43 infection. Moreover, we found that LY6E also efficiently restricted the entry mediated by the envelope spike proteins of other human coronaviruses, including the currently pandemic SARS-CoV-2. Interestingly, overexpression of serine protease TMPRSS2 or amphotericin treatment significantly neutralized the IFN-inducible transmembrane 3 (IFITM3) restriction of human coronavirus (CoV) entry, but did not compromise the effect of LY6E on the entry of human coronaviruses. The work reported herein thus demonstrates that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis via a mechanism distinct from other factors that modulate CoV entry.IMPORTANCE Virus entry into host cells is one of the key determinants of host range and cell tropism and is subjected to the control of host innate and adaptive immune responses. In the last decade, several interferon-inducible cellular proteins, including IFITMs, GILT, ADAP2, 25CH, and LY6E, had been identified to modulate the infectious entry of a variety of viruses. Particularly, LY6E was recently identified as a host factor that facilitates the entry of several human-pathogenic viruses, including human immunodeficiency virus, influenza A virus, and yellow fever virus. Identification of LY6E as a potent restriction factor of coronaviruses expands the biological function of LY6E and sheds new light on the immunopathogenesis of human coronavirus infection. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/32641482/LY6E_Restricts_Entry_of_Human_Coronaviruses_Including_Currently_Pandemic_SARS_CoV_2_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=32641482 DB - PRIME DP - Unbound Medicine ER -