Cellular Importin-?3 Expression Dynamics in the Lung Regulate Antiviral Response Pathways against Influenza A Virus Infection.

ABSTRACT: Importin-? adaptor proteins orchestrate dynamic nuclear transport processes involved in cellular homeostasis. Here, we show that importin-?3, one of the main NF-?B transporters, is the most abundantly expressed classical nuclear transport factor in the mammalian respiratory tract. Importin-?3 promoter activity is regulated by TNF-?-induced NF-?B in a concentration-dependent manner. High-level TNF-?-inducing highly pathogenic avian influenza A viruses (HPAIVs) isolated from fatal human cases harboring human-type polymerase signatures (PB2 627K, 701N) significantly downregulate importin-?3 mRNA expression in primary lung cells. Importin-?3 depletion is restored upon back-mutating the HPAIV polymerase into an avian-type signature (PB2 627E, 701D) that can no longer induce high TNF-? levels. Importin-?3-deficient mice show reduced NF-?B-activated antiviral gene expression and increased influenza lethality. Thus, importin-?3 plays a key role in antiviral immunity against influenza. Lifting the bottleneck in importin-?3 availability in the lung might provide a new strategy to combat respiratory virus infections.

SUBMITTER: Thiele S 

PROVIDER: S-EPMC7172908 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature