Human Heat shock protein 40 (Hsp40/DnaJB1) promotes influenza A virus replication by assisting nuclear import of viral ribonucleoproteins.

Jyoti Batra,Suryaprakash Sambhara,Amrita Kumar,Renu B Lal,Nancy J Cox,Jacqueline M Katz,Sunil K Lal,Shashank Tripathi

doi:10.1038/srep19063

Abstract

A unique feature of influenza A virus (IAV) life cycle is replication of the viral genome in the host cell nucleus. The nuclear import of IAV genome is an indispensable step in establishing virus infection. IAV nucleoprotein (NP) is known to mediate the nuclear import of viral genome via its nuclear localization signals. Here, we demonstrate that cellular heat shock protein 40 (Hsp40/DnaJB1) facilitates the nuclear import of incoming IAV viral ribonucleoproteins (vRNPs) and is important for efficient IAV replication. Hsp40 was found to interact with NP component of IAV RNPs during early stages of infection. This interaction is mediated by the J domain of Hsp40 and N-terminal region of NP. Drug or RNAi mediated inhibition of Hsp40 resulted in reduced nuclear import of IAV RNPs, diminished viral polymerase function and attenuates overall viral replication. Hsp40 was also found to be required for efficient association between NP and importin alpha, which is crucial for IAV RNP nuclear translocation. These studies demonstrate an important role for cellular chaperone Hsp40/DnaJB1 in influenza A virus life cycle by assisting nuclear trafficking of viral ribonucleoproteins.

Highlights

The compact genome of viruses restricts their ability to encode all the proteins required for their efficient replication
influenza A virus (IAV) RNA is transcribed and replicated in the nucleus and nucleocytoplasmic shuttling of viral ribonucleoproteins (vRNPs) is a crucial process in virus replication
New NP is translated from viral mRNAs in the cytoplasm and transported to nucleus to spur the process of transcription and replication of viral genome[54,55]

Summary

Introduction

The compact genome of viruses restricts their ability to encode all the proteins required for their efficient replication. Cellular chaperones are one of the most commonly targeted classes of host proteins which are subverted by viruses[1] These ubiquitously expressed proteins include a diverse set of heat shock proteins which play important roles in multiple cellular processes such as protein translation, folding, degradation, intracellular trafficking and stress response[2,3,4,5]. In the case of influenza virus, Hsp[90] and Hsp[70] have been shown to interact with polymerase subunits and have been suggested to be involved in assembly and nuclear transport of viral polymerase subunits, possibly by acting as a molecular chaperone for the viral polymerase complex[31,32]. Hsp[40] was found to facilitate the interaction between NP and importin alpha These findings suggest an important role of cellular chaperone Hsp40/DnaJB1 in the influenza virus replication and establish Hsp[40] as a promising antiviral target

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Results

Conclusion