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<p>Influenza A virus (IAV) hijacks host cellular machinery during infection but many host–virus protein interactions remain uncharacterized, particularly in their native context. Here, we applied in-cell cross-linking mass spectrometry, integrated with structural modelling and functional assays, to map protein–protein contact sites in IAV-infected human cells. This revealed previously unrecognized virus–host interactions linked to spatially organized processes. We identified host factors linked to the maturation of distinct glycoforms of the viral surface glycoprotein haemagglutinin through the membrane-bound endoplasmic reticulum–Golgi system. In the nucleus, we observed the progressive disassembly of paraspeckles (phase-separated membraneless compartments) across multiple cell lines. Mechanistically, viral nucleoprotein and non-structural protein 1 interact with host paraspeckle proteins, the viral endonuclease PA-X degrades long non-coding RNA housed within paraspeckles and viral RNA polymerase II is inhibited to drive paraspeckle disruption, which releases host factors that facilitate IAV replication. These findings uncover mechanisms by which IAV exploits and remodels host compartments during infection.</p>

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Mapping in-cell protein contact sites reveals hijacking of paraspeckles during influenza A virus infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Iuliia Kotova,
  • Lars Mühlberg,
  • Konstantin Gilep,
  • Mira Lea Burtscher,
  • Isabelle Becher,
  • Dingquan Yu,
  • Daniel Ziemianowicz,
  • Stephanie Stanelle-Bertram,
  • Sebastian Beck,
  • Kyungmin Baeg,
  • Alexandra Grba,
  • Olivier Duss,
  • Gülşah Gabriel,
  • Mikhail M. Savitski,
  • Fan Liu,
  • Boris Bogdanow,
  • Jan Kosinski

摘要

Influenza A virus (IAV) hijacks host cellular machinery during infection but many host–virus protein interactions remain uncharacterized, particularly in their native context. Here, we applied in-cell cross-linking mass spectrometry, integrated with structural modelling and functional assays, to map protein–protein contact sites in IAV-infected human cells. This revealed previously unrecognized virus–host interactions linked to spatially organized processes. We identified host factors linked to the maturation of distinct glycoforms of the viral surface glycoprotein haemagglutinin through the membrane-bound endoplasmic reticulum–Golgi system. In the nucleus, we observed the progressive disassembly of paraspeckles (phase-separated membraneless compartments) across multiple cell lines. Mechanistically, viral nucleoprotein and non-structural protein 1 interact with host paraspeckle proteins, the viral endonuclease PA-X degrades long non-coding RNA housed within paraspeckles and viral RNA polymerase II is inhibited to drive paraspeckle disruption, which releases host factors that facilitate IAV replication. These findings uncover mechanisms by which IAV exploits and remodels host compartments during infection.