HCMV-induced signaling through gB-EGFR engagement is required for viral trafficking and nuclear translocation in primary human monocytes.

Autor:	Fulkerson HL; Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103.; Center for Molecular & Tumor Virology, Center for Cardiovascular Diseases & Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103., Chesnokova LS; Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103., Kim JH; Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103.; Institute of Endemic Diseases, Seoul National University Medical Research Center, 03080 Seoul, Republic of Korea., Mahmud J; Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210., Frazier LE; Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103., Chan GC; Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210., Yurochko AD; Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103; ayuroc@lsuhsc.edu.; Center for Molecular & Tumor Virology, Center for Cardiovascular Diseases & Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103.; Feist-Weiller Cancer Center, Center for Excellence in Arthritis and Rheumatology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Aug 11; Vol. 117 (32), pp. 19507-19516. Date of Electronic Publication: 2020 Jul 28.
DOI:	10.1073/pnas.2003549117
Abstrakt:	Previous analysis of postentry events revealed that human cytomegalovirus (HCMV) displays a unique, extended nuclear translocation pattern in monocytes. We determined that c-Src signaling through pentamer engagement of integrins is required upon HCMV entry to avoid sorting of the virus into late endosomes and subsequent degradation. To follow up on this previous study, we designed experiments to investigate how HCMV-induced signaling through the other major axis-the epidermal growth factor receptor (EGFR) kinase-regulates viral postentry events. Here we show that HCMV induces chronic and functional EGFR signaling that is distinct to the virus as compared to the natural EGFR ligand: EGF. This chronic EGFR kinase activity in infected monocytes is required for the proper subcellular localization of the viral particle during trafficking events, as well as for promoting translocation of viral DNA into the host nucleus. Our data indicate that HCMV glycoprotein B (gB) binds to EGFR at the monocyte surface, the virus and EGFR are internalized together, and gB remains bound to EGFR throughout viral postentry events until de-envelopment to promote the chronic EGFR kinase activity required for viral trafficking and nuclear translocation. These data highlight how initial EGFR signaling via viral binding is necessary for entry, but not sufficient to promote each viral trafficking event. HCMV appears to manipulate the EGFR kinase postentry, via gB-EGFR interaction, to be active at the critical points throughout the trafficking process that leads to nuclear translocation and productive infection of peripheral blood monocytes. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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