Irreversible furin cleavage site exposure renders immature tick-borne flaviviruses fully infectious
Flavivirus assembly is driven by the envelope glycoproteins pre-membrane (prM) and envelope (E) in the neutral pH environment of the endoplasmic reticulum. Newly budded, spiky particles are exported through the Golgi apparatus, where mildly acidic pH induces a major surface rearrangement. The glycoproteins reorganize into (prM/E)\₂ complexes at the surface of smooth particles, with prM trapped at the E dimer interface, thereby exposing a furin cleavage site (FCS) for proteolytic maturation into infectious virions. Here, we show that in the absence of furin, immature tick-borne flavivirus particles-tick-borne encephalitis virus, Langat virus, and Louping ill virus-remain fully infectious and pathogenic in female BALB/c mice, in contrast to mosquito-borne flaviviruses such as Usutu, West Nile, and Zika viruses. We further show that the FCS in tick-borne viruses remains exposed at neutral pH, allowing furin at the surface of target cells to activate viral fusogenicity, while mosquito-borne counterparts require acidic re-exposure. Mutations increasing the dynamic behavior of the E dimer mimic the mosquito-borne phenotype, with retracted FCS at neutral pH and loss of infectivity. Our multidisciplinary approach-combining virological assays, targeted mutagenesis, structural modeling, and molecular dynamics simulations-highlights the role of E dimer dynamics in regulating flavivirus maturation and infectivity.
Authors
- Milos Matkovic (ORCID: https://orcid.org/0000-0002-4872-1996)
- Jiřı́ Salát (ORCID: https://orcid.org/0000-0002-9915-8953)
- Jiří Holoubek (ORCID: https://orcid.org/0009-0000-7850-7723)
- Martin Hradílek (ORCID: https://orcid.org/0000-0003-2852-7026)
- F.A. Rey (ORCID: https://orcid.org/0000-0002-9953-7988)
- Anna K. Överby (ORCID: https://orcid.org/0000-0001-6553-0940)
- Petr Bednář (ORCID: https://orcid.org/0000-0003-4924-3663)
- Taťána Majerová (ORCID: https://orcid.org/0000-0001-5536-3587)
- Luděk Eyer (ORCID: https://orcid.org/0000-0001-7761-0702)
- Massimiliano Bonomi (ORCID: https://orcid.org/0000-0002-7321-0004)
- Pavel Novotný (ORCID: https://orcid.org/0000-0001-7325-6961)
- Ebba Rosendal (ORCID: https://orcid.org/0000-0001-8512-0535)
- Andrea Fořtová (ORCID: https://orcid.org/0009-0003-8701-7867)
- Andrea Cavalli (ORCID: https://orcid.org/0000-0003-4063-4502)
- Daniel Růžek (ORCID: https://orcid.org/0000-0003-4655-2380)
- Michaela Beránková
- Lesley Bell-Sakyi
Institutions
- SIB Swiss Institute of Bioinformatics (CH)
- Centre National de la Recherche Scientifique (FR)
- University of Liverpool (GB)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- Charles University (CZ)
- Masaryk University (CZ)
- Institute of Parasitology of the Slovak Academy of Sciences (SK)
- Veterinary Research Institute (CZ)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- Università della Svizzera italiana (CH)
- Umeå University (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s41467-025-62750-6
- Citations
- 3
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Univerzita Karlova v Praze
- Grantová Agentura, Univerzita Karlova
- Wellcome Trust
- European Commission
- Grantová Agentura České Republiky
- Vetenskapsrådet
- EEA Grants/Norway Grants