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Abstract
Influenza A virus (IAV), like other viruses, depends on the host cellular machinery for replication and production of progeny. The relationship between a virus and a host is complex, shaped by many spatial and temporal interactions between viral and host proteome, ultimately dictating disease outcome. Therefore, it is imperative to identify host-virus interactions as crucial determinants of disease pathogenies. Heterogeneous ribonucleoprotein A1 (hnRNPA1) is an RNA binding protein involved in the life cycle of many DNA and RNA viruses; however, its role in IAV remains undiscovered. Here we report that human hnRNPA1 physically interacts with the nucleoprotein (NP) of IAV in mammalian cells at different time points of the viral replication cycle. Temporal distribution studies identify hnRNPA1 and NP co-localize in the same cellular milieu in both nucleus and mitochondria in NP-transfected and IAV-infected mammalian cells. Interestingly, hnRNPA1 influenced NP gene expression and affected viral replication. Most importantly, hnRNPA1 knockdown caused a significant increase in NP expression and enhanced viral replication (93.82%) in IAV infected A549 cells. Conversely, hnRNPA1 overexpression reduced NP expression at the mRNA and protein levels and impeded virus replication by (60.70%), suggesting antagonistic function. Taken together, results from this study demonstrate that cellular hnRNPA1 plays a protective role in the host hitherto unknown and may hold potential as an antiviral target to develop host-based therapeutics against IAV.
Highlights
Influenza A is a zoonotic intracellular RNA virus that imposes a significant disease burden, with approximately 3–5 million infections annually worldwide
We have shown that Heterogeneous ribonucleoprotein A1 (hnRNPA1) overexpression attenuates NP gene expression at mRNA and protein level and abrogates viral replication
Our results demonstrate a novel role of human hnRNPA1 in the Influenza A virus (IAV) replication
Summary
Influenza A is a zoonotic intracellular RNA virus that imposes a significant disease burden, with approximately 3–5 million infections annually worldwide. Multiple studies have suggested that NP functions as an adapter protein at the center of host-virus interactions [6–8]. HnRNPA1 is the most ubiquitously expressed member of the hnRNP A/B subfamily, known to regulate various aspects of RNA metabolism and gene expression [18,19]. Multiple hnRNP family members like hnRNP M, H1, A2B1, AB are reported to interact with IAV proteins and regulate viral replication [21–24]. There is mounting evidence that hnRNPA1, an RNA binding protein, interacts with many viral gene products and differentially regulates host-virus gene expression in viral infections [14,31]. We have shown that hnRNPA1 overexpression attenuates NP gene expression at mRNA and protein level and abrogates viral replication. Downregulation of hnRNPA1 enhanced NP gene expression and progeny virion production in IAV-infected cells. Our results demonstrate a novel role of human hnRNPA1 in the IAV replication
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