tetano
Editor, Senior Moderator
Cell Rep. 2020 Apr 21;31(3):107549. doi: 10.1016/j.celrep.2020.107549.
Cellular Importin-α3 Expression Dynamics in the Lung Regulate Antiviral Response Pathways against Influenza A Virus Infection.
Thiele S[SUP]1[/SUP], Stanelle-Bertram S[SUP]1[/SUP], Beck S[SUP]1[/SUP], Kouassi NM[SUP]1[/SUP], Zickler M[SUP]1[/SUP], M?ller M[SUP]1[/SUP], Tuku B[SUP]1[/SUP], Resa-Infante P[SUP]1[/SUP], van Riel D[SUP]2[/SUP], Alawi M[SUP]3[/SUP], G?nther T[SUP]4[/SUP], Rother F[SUP]5[/SUP], H?gel S[SUP]6[/SUP], Reimering S[SUP]7[/SUP], McHardy A[SUP]7[/SUP], Grundhoff A[SUP]4[/SUP], Brune W[SUP]8[/SUP], Osterhaus A[SUP]9[/SUP], Bader M[SUP]10[/SUP], Hartmann E[SUP]11[/SUP], Gabriel G[SUP]12[/SUP].
Author information
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.
Copyright ? 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
KEYWORDS:
cytokine storm; immune sensor; influenza; lung; pneumonia
PMID:32320654PMCID:PMC7172908DOI:10.1016/j.celrep.2020.107549
Free PMC Article
Cellular Importin-α3 Expression Dynamics in the Lung Regulate Antiviral Response Pathways against Influenza A Virus Infection.
Thiele S[SUP]1[/SUP], Stanelle-Bertram S[SUP]1[/SUP], Beck S[SUP]1[/SUP], Kouassi NM[SUP]1[/SUP], Zickler M[SUP]1[/SUP], M?ller M[SUP]1[/SUP], Tuku B[SUP]1[/SUP], Resa-Infante P[SUP]1[/SUP], van Riel D[SUP]2[/SUP], Alawi M[SUP]3[/SUP], G?nther T[SUP]4[/SUP], Rother F[SUP]5[/SUP], H?gel S[SUP]6[/SUP], Reimering S[SUP]7[/SUP], McHardy A[SUP]7[/SUP], Grundhoff A[SUP]4[/SUP], Brune W[SUP]8[/SUP], Osterhaus A[SUP]9[/SUP], Bader M[SUP]10[/SUP], Hartmann E[SUP]11[/SUP], Gabriel G[SUP]12[/SUP].
Author information
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.
Copyright ? 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
KEYWORDS:
cytokine storm; immune sensor; influenza; lung; pneumonia
PMID:32320654PMCID:PMC7172908DOI:10.1016/j.celrep.2020.107549
Free PMC Article