Cell Reports (Apr 2020)

Cellular Importin-α3 Expression Dynamics in the Lung Regulate Antiviral Response Pathways against Influenza A Virus Infection

  • Swantje Thiele,
  • Stephanie Stanelle-Bertram,
  • Sebastian Beck,
  • Nancy Mounogou Kouassi,
  • Martin Zickler,
  • Martin Müller,
  • Berfin Tuku,
  • Patricia Resa-Infante,
  • Debby van Riel,
  • Malik Alawi,
  • Thomas Günther,
  • Franziska Rother,
  • Stefanie Hügel,
  • Susanne Reimering,
  • Alice McHardy,
  • Adam Grundhoff,
  • Wolfram Brune,
  • Albert Osterhaus,
  • Michael Bader,
  • Enno Hartmann,
  • Gülsah Gabriel

Journal volume & issue
Vol. 31, no. 3

Abstract

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Summary: 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. : Thiele et al. show that importin-α3 is one of the major nuclear transporters of NF-κB in the mammalian lung. High-level TNF-α-inducing HPAIVs inhibit importin-α3 mRNA transcription by interfering with its promoter activity. Thus, HPAIVs may evade antiviral immunity in the respiratory tract by generating a bottleneck in importin-α3 availability. Keywords: lung, influenza, pneumonia, immune sensor, cytokine storm