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Importin β1 targeting by hepatitis C virus NS3 / 4A protein restricts IRF3 and NF‐κB signaling of IFNB1 antiviral response
Author(s) -
Gagné Bridget,
Tremblay Nicolas,
Park Alex Y.,
Baril Martin,
Lamarre Daniel
Publication year - 2017
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/tra.12480
Subject(s) - irf3 , nuclear transport , ns3 , biology , microbiology and biotechnology , nuclear export signal , signal transducing adaptor protein , innate immune system , karyopherin , importin , tlr3 , nuclear protein , gene silencing , transcription factor , signal transduction , cell nucleus , virus , virology , hepatitis c virus , immune system , toll like receptor , cytoplasm , biochemistry , gene , immunology
In this study, newly identified host interactors of hepatitis C virus ( HCV ) proteins were assessed for a role in modulating the innate immune response. The analysis revealed enrichment for components of the nuclear transport machinery and the crucial interaction with NS3 / 4A protein in suppression of interferon‐β ( IFNB1 ) induction. Using a comprehensive microscopy‐based high‐content screening approach combined to the gene silencing of nuclear transport factors, we showed that NS3 / 4A ‐interacting proteins control the nucleocytoplasmic trafficking of IFN regulatory factor 3 ( IRF3 ) and NF‐κB p65 upon Sendai virus ( SeV ) infection. Notably, importin β1 ( IMPβ1 ) knockdown—a hub protein highly targeted by several viruses—decreases the nuclear translocation of both transcription factors and prevents IFNB1 and IFIT1 induction, correlating with a rapid increased of viral proteins and virus‐mediated apoptosis. Here we show that NS3 / 4A triggers the cleavage of IMPβ1 and inhibits nuclear transport to disrupt IFNB1 production. Importantly, mutated IMPβ1 resistant to cleavage completely restores signaling, similar to the treatment with BILN 2061 protease inhibitor, correlating with the disappearance of cleavage products. Overall, the data indicate that HCV NS3 / 4A targeting of IMPβ1 and related modulators of IRF3 and NF‐κB nuclear transport constitute an important innate immune subversion strategy and inspire new avenues for broad‐spectrum antiviral therapies.