Influenza A Virus Nucleoprotein Activates the JNK Stress-Signaling Pathway for Viral Replication by Sequestering Host Filamin A Protein.

Anshika Sharma,Matthew S Reed,Sunil K Lal,Olga Stuchlik,Jyoti Batra,Vincent T K Chow,Suryaprakash Sambhara,Jan Pohl

doi:10.3389/fmicb.2020.581867

Abstract

Influenza A virus (IAV) poses a major threat to global public health and is known to employ various strategies to usurp the host machinery for survival. Due to its fast-evolving nature, IAVs tend to escape the effect of available drugs and vaccines thus, prompting the development of novel antiviral strategies. High-throughput mass spectrometric screen of host-IAV interacting partners revealed host Filamin A (FLNA), an actin-binding protein involved in regulating multiple signaling pathways, as an interaction partner of IAV nucleoprotein (NP). In this study, we found that the IAV NP interrupts host FLNA-TRAF2 interaction by interacting with FLNA thus, resulting in increased levels of free, displaced TRAF2 molecules available for TRAF2-ASK1 mediated JNK pathway activation, a pathway critical to maintaining efficient viral replication. In addition, siRNA-mediated FLNA silencing was found to promote IAV replication (87% increase) while FLNA-overexpression impaired IAV replication (65% decrease). IAV NP was observed to be a crucial viral factor required to attain FLNA mRNA and protein attenuation post-IAV infection for efficient viral replication. Our results reveal FLNA to be a host factor with antiviral potential hitherto unknown to be involved in the IAV replication cycle thus, opening new possibilities of FLNA-NP interaction as a candidate anti-influenza drug development target.

Highlights

Influenza A viruses (IAVs) are the most popular amongst the Influenza viruses, owing to their ability to cause epidemics and pandemics (Taubenberger and Morens, 2009)
The results revealed a conservative interaction between host Filamin A (FLNA) and IAV NP, with positive FLNA-NP interaction observed across NP from the A/Puerto Rico/8/34 isolate (PR8), A/Hong Kong/1/1968 isolate (HK), and WSN strains (Figure 1A)
The IAV NP of PR8 was found to interact with human FLNA (Figure 1B) and reciprocally, FLNA was found to interact with NP from both PR8 and A/HKx31 isolate (HKX31) strains (Figure 1C)

Summary

Introduction

Influenza A viruses (IAVs) are the most popular amongst the Influenza viruses, owing to their ability to cause epidemics and pandemics (Taubenberger and Morens, 2009). Instead of targeting viral proteins, this novel pharmacological strategy aims to target essential host proteins and pathways used by the IAVs to fulfill their replicative cycle (Qian et al, 2016). This strategy aids in overcoming the serious challenge of viruses escaping from drug effects via antigenic drift or shift (Linero et al, 2012). According to Li et al (2015), the IAV NP has been reported to interact with both host and viral proteins to mediate the transport of the vRNP from the cytoplasm to the nucleus and vice versa, as well as to regulate the expression of vRNA. The sequence of NP has shown to be conserved across IAV isolates NP-host interactions serve as compelling antiviral targets (Sharma et al, 2014)

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