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Cellular importin-α3 expression dynamics in the lung regulate antiviral response pathways against influenza a virus infection

Authors

  • S. Thiele
  • S. Stanelle-Bertram
  • S. Beck
  • N. Kouassi
  • M. Zickler
  • M. Müller
  • B. Tuku
  • P. Resa-Infante
  • D. van Riel
  • M. Alawi
  • T. Günther
  • F. Rother
  • S. Hügel
  • S. Reimering
  • A. McHardy
  • A. Grundhoff
  • W. Brune
  • A. Osterhaus
  • M. Bader
  • E. Hartmann
  • G. Gabriel

Journal

  • Cell Reports

Citation

  • Cell Rep 31 (3): 107549

Abstract

  • Importin-α adaptor proteins orchestrate dynamic nuclear transport processes involved in cellular homeostasis. Here, we show that importin-α3, one of the main NF-κB transporters, is the most abundantly expressed classical nuclear transport factor in the mammalian respiratory tract. Importin-α3 promoter activity is regulated by TNF-α-induced NF-κB in a concentration-dependent manner. High-level TNF-α-inducing highly pathogenic avian influenza A viruses (HPAIVs) isolated from fatal human cases harboring human-type polymerase signatures (PB2 627K, 701N) significantly downregulate importin-α3 mRNA expression in primary lung cells. Importin-α3 depletion is restored upon back-mutating the HPAIV polymerase into an avian-type signature (PB2 627E, 701D) that can no longer induce high TNF-α levels. Importin-α3-deficient mice show reduced NF-κB-activated antiviral gene expression and increased influenza lethality. Thus, importin-α3 plays a key role in antiviral immunity against influenza. Lifting the bottleneck in importin-α3 availability in the lung might provide a new strategy to combat respiratory virus infections.


DOI

doi:10.1016/j.celrep.2020.107549