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

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Item Type:Article
Title:Cellular importin-α3 expression dynamics in the lung regulate antiviral response pathways against influenza a virus infection
Creators Name:Thiele, S. and Stanelle-Bertram, S. and Beck, S. and Kouassi, N. and Zickler, M. and Müller, M. and Tuku, B. and Resa-Infante, P. and van Riel, D. and Alawi, M. and Günther, T. and Rother, F. and Hügel, S. and Reimering, S. and McHardy, A. and Grundhoff, A. and Brune, W. and Osterhaus, A. and Bader, M. and Hartmann, E. and Gabriel, G.
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.
Keywords:Lung, Influenza, Pneumonia, Immune Sensor, Cytokine Storm, Animals, Mice
Source:Cell Reports
ISSN:2211-1247
Publisher:Cell Press / Elsevier
Volume:31
Number:3
Page Range:107549
Date:21 April 2020
Official Publication:https://doi.org/10.1016/j.celrep.2020.107549
PubMed:View item in PubMed

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