{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:29:55Z","timestamp":1792013395543,"version":"4.4.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"5","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,1,29]]},"abstract":"<jats:p>\n                    Herpesvirus entry functions of the conserved glycoproteins gB and gH\u2013gL have been delineated, but their role in regulating cell\u2013cell fusion is poorly understood. Varicella-zoster virus (VZV) infection provides a valuable model for investigating cell\u2013cell fusion because of the importance of this process for pathogenesis in human skin and sensory ganglia. The present study identifies a canonical immunoreceptor tyrosine-based inhibition motif (ITIM) in the gB cytoplasmic domain (gB\n                    <jats:italic>cyt<\/jats:italic>\n                    ) and demonstrates that the gB\n                    <jats:italic>cyt<\/jats:italic>\n                    is a tyrosine kinase substrate. Orbitrap mass spectrometry confirmed that Y881, central to the ITIM, is phosphorylated. To determine whether the gB\n                    <jats:italic>cyt<\/jats:italic>\n                    ITIM regulates gB\/gH\u2013gL\u2013induced cell\u2013cell fusion in vitro, tyrosine residues Y881 and Y920 in the gB\n                    <jats:italic>cyt<\/jats:italic>\n                    were substituted with phenylalanine separately or together. Recombinant viruses with these substitutions were generated to establish their effects on syncytia formation in replication in vitro and in the human skin xenograft model of VZV pathogenesis. The Y881F substitution caused significantly increased cell\u2013cell fusion despite reduced cell-surface gB. Importantly, the Y881F or Y881\/920F substitutions in VZV caused aggressive syncytia formation, reducing cell\u2013cell spread. These in vitro effects of aggressive syncytia formation translated to severely impaired skin infection in vivo. In contrast, the Y920F substitution did not affect virus replication in vitro or in vivo. These observations suggest that gB modulates cell\u2013cell fusion via an ITIM-mediated Y881 phosphorylation-dependent mechanism, supporting a unique concept that intracellular signaling through this gB\n                    <jats:italic>cyt<\/jats:italic>\n                    motif regulates VZV syncytia formation and is essential for skin pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1216985110","type":"journal-article","created":{"date-parts":[[2013,1,16]],"date-time":"2013-01-16T00:21:16Z","timestamp":1358295676000},"page":"1911-1916","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":42,"title":["An immunoreceptor tyrosine-based inhibition motif in varicella-zoster virus glycoprotein B regulates cell fusion and skin pathogenesis"],"prefix":"10.1073","volume":"110","author":[{"given":"Stefan L.","family":"Oliver","sequence":"first","affiliation":[{"name":"Departments of aPediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Brady","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin H.","family":"Sommer","sequence":"additional","affiliation":[{"name":"Departments of aPediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Reichelt","sequence":"additional","affiliation":[{"name":"Departments of aPediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Sung","sequence":"additional","affiliation":[{"name":"Departments of aPediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Blau","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann M.","family":"Arvin","sequence":"additional","affiliation":[{"name":"Departments of aPediatrics and"},{"name":"Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,1,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040634"},{"key":"e_1_3_3_2_2","first-page":"2773","volume-title":"Fields\u2019 Virology","author":"Cohen JI","year":"2007","unstructured":"JI Cohen, SE Straus, A Arvin, Varicella-zoster virus replication, pathogenesis and management. 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