Irreversible furin cleavage site exposure renders immature tick-borne flaviviruses fully infectious

Jiří Holoubek, Jiří Salát, Milos Matkovic, Petr Bednář, Pavel Novotný, Martin Hradilek, Taťána Majerová, Ebba Rosendal, Luděk Eyer, Andrea Fořtová, Michaela Beránková, Lesley Bell-Sakyi, Anna K. Överby, Andrea Cavalli, Massimiliano Bonomi, Félix A. Rey () and Daniel Růžek ()
Additional contact information
Jiří Holoubek: Masaryk University
Jiří Salát: Masaryk University
Milos Matkovic: Università della Svizzera Italiana
Petr Bednář: Masaryk University
Pavel Novotný: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Martin Hradilek: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Taťána Majerová: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Ebba Rosendal: Umeå University
Luděk Eyer: Masaryk University
Andrea Fořtová: Masaryk University
Michaela Beránková: Masaryk University
Lesley Bell-Sakyi: University of Liverpool
Anna K. Överby: Umeå University
Andrea Cavalli: Università della Svizzera Italiana
Massimiliano Bonomi: Computational Structural Biology Unit
Félix A. Rey: Structural Virology Unit
Daniel Růžek: Masaryk University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62750-6

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