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BARF1 and M-CSF form a high-affinity, stable, ring-like complex in both solution and the crystal, with a BARF1 hexameric ring surrounded by three M-CSF dimers in triangular array. The binding of BARF1 to M-CSF dramatically reduces but does not completely abolish M-CSF binding and signaling through its cognate receptor FMS. A three-pronged down-regulation mechanism is proposed to explain the biological effect of BARF1 on M-CSF:FMS signaling. These prongs entail control of the circulating and effective local M-CSF concentration, perturbation of the receptor-binding surface of M-CSF, and imposition of an unfavorable global orientation of the M-CSF dimer. Each prong may reduce M-CSF:FMS signaling to a limited extent but in combination may alter M-CSF:FMS signaling dramatically. The downregulating mechanism of BARF1 underlines a viral modulation strategy, and provides a basis for understanding EBV pathogenesis.<\/jats:p>","DOI":"10.1073\/pnas.1205309109","type":"journal-article","created":{"date-parts":[[2012,7,24]],"date-time":"2012-07-24T00:48:19Z","timestamp":1343090899000},"page":"12962-12967","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Multipronged attenuation of macrophage-colony stimulating factor signaling by Epstein\u2013Barr virus BARF1"],"prefix":"10.1073","volume":"109","author":[{"given":"Ann Hye-Ryong","family":"Shim","sequence":"first","affiliation":[{"name":"Departments of aMolecular Pharmacology and Biological Chemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhoda Ahn","family":"Chang","sequence":"additional","affiliation":[{"name":"Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of aMolecular Pharmacology and Biological Chemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Longnecker","sequence":"additional","affiliation":[{"name":"Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"He","sequence":"additional","affiliation":[{"name":"Departments of aMolecular Pharmacology and Biological Chemistry and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,7,23]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"ED Kieff AB Rickinson Epstein-Barr virus and its replication. 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