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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • 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,
  • Daniel Růžek

摘要

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.