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virus (ANDV) nonlytically infects pulmonary microvascular endothelial cells (PMECs), causing acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). In HPS patients, virtually every PMEC is infected; however, the mechanism by which ANDV induces vascular permeability and edema remains to be resolved. The ANDV nucleocapsid (N) protein activates the GTPase RhoA in primary human PMECs, causing VE-cadherin internalization from adherens junctions and PMEC permeability. We found that ANDV N protein failed to bind RhoA but coprecipitates RhoGDI (Rho GDP dissociation inhibitor), the primary RhoA repressor that normally sequesters RhoA in an inactive state. ANDV N protein selectively binds the RhoGDI C terminus (residues 69 to 204) but fails to form ternary complexes with RhoA or inhibit RhoA binding to the RhoGDI N terminus (residues 1 to 69). However, we found that ANDV N protein uniquely inhibits RhoA binding to an S34D phosphomimetic RhoGDI mutant. Hypoxia and vascular endothelial growth factor (VEGF) increase RhoA-induced PMEC permeability by directing protein kinase C\u03b1 (PKC\u03b1) phosphorylation of S34 on RhoGDI. Collectively, ANDV N protein alone activates RhoA by sequestering and reducing RhoGDI available to suppress RhoA. In response to hypoxia and VEGF-activated PKC\u03b1, ANDV N protein additionally directs the release of RhoA from S34-phosphorylated RhoGDI, synergistically activating RhoA and PMEC permeability. These findings reveal a fundamental edemagenic mechanism that permits ANDV to amplify PMEC permeability in hypoxic HPS patients. Our results rationalize therapeutically targeting PKC\u03b1 and opposing protein kinase A (PKA) pathways that control RhoGDI phosphorylation as a means of resolving ANDV-induced capillary permeability, edema, and HPS. <b>IMPORTANCE</b> HPS-causing hantaviruses infect pulmonary endothelial cells (ECs), causing vascular leakage, pulmonary edema, and a 35% fatal acute respiratory distress syndrome (ARDS). Hantaviruses do not lyse or disrupt the endothelium but dysregulate normal EC barrier functions and increase hypoxia-directed permeability. Our findings reveal a novel underlying mechanism of EC permeability resulting from ANDV N protein binding to RhoGDI, a regulatory protein that normally maintains edemagenic RhoA in an inactive state and inhibits EC permeability. ANDV N sequesters RhoGDI and enhances the release of RhoA from S34-phosphorylated RhoGDI. These findings indicate that ANDV N induces the release of RhoA from PKC-phosphorylated RhoGDI, synergistically enhancing hypoxia-directed RhoA activation and PMEC permeability. Our data suggest inhibiting PKC and activating PKA phosphorylation of RhoGDI as mechanisms of inhibiting ANDV-directed EC permeability and therapeutically restricting edema in HPS patients. These findings may be broadly applicable to other causes of ARDS.","bibjson":{"author":[{"initials":"Q","lastname":"Zhang","name":"Zhang Q"},{"initials":"K","lastname":"Liu","name":"Liu K"},{"initials":"C","lastname":"Yue","name":"Yue C"},{"initials":"D","lastname":"Zhang","name":"Zhang D"},{"initials":"D","lastname":"Lu","name":"Lu D"},{"initials":"W","lastname":"Xiao","name":"Xiao W"},{"initials":"P","lastname":"Liu","name":"Liu P"},{"initials":"Y","lastname":"Zhao","name":"Zhao Y"},{"initials":"G","lastname":"Gao","name":"Gao G"},{"initials":"C","lastname":"Ding","name":"Ding C"},{"initials":"J","lastname":"Lyu","name":"Lyu J"},{"initials":"WJ","lastname":"Liu","name":"Liu WJ"}],"identifier":[{"id":"10.1128/jvi.00396-20","type":"doi"},{"id":"32522857","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. 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