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Prior proteomic studies mapped such interactions for some flaviviruses, but yellow fever virus (YFV)\u2014a pathogen of resurgent concern\u2014remains understudied. Here, we map YFV interactomes in human and mosquito cells to identify interactions common among divergent flaviviruses or unique to YFV. Functional assays reveal a previously unrecognized YFV restriction factor: RBBP6 inhibits YFV genome replication by interacting with the viral polymerase NS5. We enhance the identification of dual-host interactions using structural modeling and holistic network integration. Extending our holistic approach to other flavivirus interactomes, we distinguish conserved mechanisms of host targeting from those unique to YFV. Contrary to expectations that conserved viral proteins lead to conserved protein interactions, we find that Capsid, a divergent structural protein, shares more host interactions than NS5, a conserved enzyme. Integrating proteomics with complementary analyses defines new principles of host-targeting strategies across flavivirus and host evolution, offering a versatile resource for navigating the complex landscape of flavivirus biology.<\/jats:p>","DOI":"10.1101\/2025.06.14.659623","type":"posted-content","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T01:05:16Z","timestamp":1750295116000},"source":"Crossref","is-referenced-by-count":2,"title":["Yellow Fever Virus Interactomes Reveal Common and Divergent Strategies of Replication and Evolution for Mosquito-borne Flaviviruses"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8820-227X","authenticated-orcid":false,"given":"Matthew W.","family":"Kenaston","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of California, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liubov","family":"Cherkashchenko","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of California, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chase L. 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