Abstract
BackgroundThe influenza A virus NS1 protein is a virulence factor and an antagonist of host cell innate immune responses. During virus infection NS1 protein has several functions both in the nucleus and in the cytoplasm and its intracellular localization is regulated by one or two nuclear localization signals (NLS) and a nuclear export signal (NES).MethodsIn order to investigate the role of NS1 NES in intracellular localization, virus life cycle and host interferon responses, we generated recombinant A/Udorn/72 viruses harboring point mutations in the NES sequence.ResultsNS1 NES was found to be inactivated by several of the mutations resulting in nuclear retention of NS1 at late stages of infection confirming that this sequence is a bona fide functional NES. Some of the mutant viruses showed reduced growth properties in cell culture, inability to antagonize host cell interferon production and increased p-IRF3 levels, but no clear correlation between these phenotypes and NS1 localization could be made. Impaired activation of Akt phosphorylation by the replication-deficient viruses indicates possible disruption of NS1-p85β interaction by mutations in the NES region.ConclusionWe conclude that mutations within the NS1 NES result in impairment of several NS1 functions which extends further from the NES site being only involved in regulating the nuclear-cytoplasmic trafficking of NS1.
Highlights
The influenza A virus NS1 protein is a virulence factor and an antagonist of host cell innate immune responses
The NS1 nuclear export signal (NES) is located in the middle of the effector domain and comprises of a phenylalanine and three leucines each separated by one or two amino acids (Figure 1A)
In order to determine the conservation rate of the NS1 NES we compared more than 25,000 influenza A NS1 amino acid sequences available in the Influenza Research Database [21] using the sequence variation analysis tool accessible on the website http://www.fludb.org (Table 1)
Summary
The influenza A virus NS1 protein is a virulence factor and an antagonist of host cell innate immune responses. During virus infection NS1 protein has several functions both in the nucleus and in the cytoplasm and its intracellular localization is regulated by one or two nuclear localization signals (NLS) and a nuclear export signal (NES). Influenza A virus has a segmented genome consisting of eight single stranded negative-sense RNA molecules, which encode for 14 different proteins. Some of these proteins, such as the HA, PB1-F2 and NS1 proteins contribute to the virulence of the virus [1]. Localization studies have shown that NS1 localizes predominantly in the nucleus, but it is translocated into the cytoplasm at late stages of infection possibly due to the unmasking of NES or, in the event of a competitive relationship between NLS and NES, perhaps because of masking of the NLS signals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
