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Hemorrhage across different organs is a hallmark pathological feature of orbivirus infection, as exemplified by the bluetongue virus (BTV); however, the underlying mechanisms for this feature remain unclear. This study unravels a previously unrecognized extracellular role of orbivirus nonstructural protein 3 (NS3), which hijacks the conventional secretion pathway and utilizes phosphatidylinositol (4,5)\u2010bisphosphate to travel across the plasma membrane, ultimately inducing vascular permeability and leakage. Site\u2010directed mutagenesis reveals a conserved lysine or arginine residue adjacent to the second transmembrane domain of orbivirus NS3 as being critical for secretion. Notably, a single lysine mutation impairing NS3 secretion in BTV has no effect on viral infection in vitro but abolishes vascular leakage in the spleen and lungs, rendering the virus completely avirulent in AG129 mice. This study reveals the extracellular functions of orbivirus NS3, providing critical novel insights into the molecular mechanisms driving the hemorrhagic pathology characteristic of orbivirus infections.\n                  <\/jats:p>","DOI":"10.1002\/advs.75255","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T10:47:31Z","timestamp":1776077251000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Secreted Nonstructural Protein 3 is a Pathogenic Determinant of\n                    <i>Orbivirus<\/i>"],"prefix":"10.1002","volume":"13","author":[{"given":"Junyong","family":"Guan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention Harbin Veterinary Research Institute Chinese Academy of Agricultural Sciences  Harbin 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