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During blood feeding, mosquitoes inoculate saliva containing various proteins. Recently, AgBR1, an\n              <jats:italic toggle=\"yes\">Aedes aegypti<\/jats:italic>\n              salivary gland protein, has gained attention for its immunomodulatory potential, along with another protein, called NeSt1. We have determined the crystal structure of AgBR1 at 1.2 \u00c5 resolution. Despite its chitinase-like fold, we demonstrated that AgBR1 does not bind to chitobiose or chitinhexaose, while a key mutation in the catalytic site abrogates enzymatic activity, suggesting that the protein\u2019s function has been repurposed. Our study also shows that AgBR1 and NeSt1, when presented to murine primary macrophages, alter cellular pathways related to virus entry by endocytosis, immune response, and cell proliferation. AgBR1 (and NeSt1) do not directly bind to the Zika virus or modulate its replication. We propose that their immunomodulatory effects on Zika virus transmission are through regulation of host-cell response, a consequence of evolutionary cross talk and virus opportunism. These structural and functional insights are prerequisites for developing strategies to halt the spread of mosquito-borne disease.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>Our study informs on the structural and functional significance of a mosquito salivary gland protein, AgBR1 (along with another protein called NeSt1), in the transmission of the Zika virus (ZIKV), a mosquito-borne virus that has caused global health concerns. By analyzing AgBR1\u2019s three-dimensional structure in combination with cellular and interaction studies, we discovered that AgBR1 does not function like typical proteins in its family\u2014it does not degrade sugars. However, we show that it primes immune cells in a way that could help the virus enter cells more easily but not by interacting with the virus or altering viral replication. This finding is significant because it reveals how mosquito proteins, repurposed by evolution, can influence virus transmission without the virus\u2019s direct presence. Understanding how proteins like AgBR1 work could guide the development of new strategies to prevent Zika virus spread, with potential relevance for other mosquito-borne viruses.<\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01878-24","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T13:00:24Z","timestamp":1745499624000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Structural and functional significance of\n            <i>Aedes aegypti<\/i>\n            AgBR1 flavivirus immunomodulator"],"prefix":"10.1128","volume":"99","author":[{"given":"Ane","family":"Martinez-Castillo","sequence":"first","affiliation":[{"name":"Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE) - Basque Research and Technology Alliance (BRTA)","place":["Derio, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Barriales","sequence":"additional","affiliation":[{"name":"Inflammation and Macrophage Plasticity Laboratory, CIC bioGUNE - BRTA","place":["Derio, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikel","family":"Azkargorta","sequence":"additional","affiliation":[{"name":"Proteomics Platform, CIC bioGUNE - BRTA","place":["Derio, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Diego","family":"Zalamea","sequence":"additional","affiliation":[{"name":"Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE) - Basque Research and Technology Alliance (BRTA)","place":["Derio, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ard\u00e1","sequence":"additional","affiliation":[{"name":"Chemical Glycobiology Laboratory, CIC bioGUNE - BRTA","place":["Derio, Spain"]},{"name":"IKERBASQUE, Basque Foundation for Science","place":["Bilbao, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus","family":"Jimenez-Barbero","sequence":"additional","affiliation":[{"name":"Chemical Glycobiology Laboratory, CIC bioGUNE - BRTA","place":["Derio, Spain"]},{"name":"IKERBASQUE, Basque Foundation for Science","place":["Bilbao, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Gonzalez-Lopez","sequence":"additional","affiliation":[{"name":"Genome Analysis Platform, CIC bioGUNE - BRTA","place":["Derio, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Aransay","sequence":"additional","affiliation":[{"name":"Genome Analysis Platform, CIC bioGUNE - BRTA","place":["Derio, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Mar\u00edn-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Section of Infectious Diseases, Department of Internal Medicine, School of Medicine, Yale University","place":["New Haven, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5884-6047","authenticated-orcid":true,"given":"Erol","family":"Fikrig","sequence":"additional","affiliation":[{"name":"Section of Infectious Diseases, Department of Internal Medicine, School of Medicine, Yale University","place":["New Haven, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Elortza","sequence":"additional","affiliation":[{"name":"Proteomics Platform, CIC bioGUNE - BRTA","place":["Derio, Spain"]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2061-7182","authenticated-orcid":true,"given":"Juan","family":"Anguita","sequence":"additional","affiliation":[{"name":"Inflammation and Macrophage Plasticity Laboratory, CIC bioGUNE - BRTA","place":["Derio, Spain"]},{"name":"IKERBASQUE, Basque Foundation for Science","place":["Bilbao, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5559-1918","authenticated-orcid":true,"given":"Nicola G. 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