Heterogeneous Ribonucleoprotein A1 (hnRNPA1) Interacts with the Nucleoprotein of the Influenza a Virus and Impedes Virus Replication

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.

Diverse roles of heterogeneous nuclear ribonucleoproteins in viral life cycle

“…hnRNP A1 interacts with p17 protein of avian reovirus (ARV) to facilities its nuclear import and export (218). hnRNP A1 also interacts with nucleoprotein (NP) of IAV and co-localize in both nucleus and mitochondria of mammalian cells that are either transfected with NP or infected with IAV (219). Similarly, hnRNP A1 interacts with nucleocapsid (N) protein of porcine epidemic diarrhea virus (PEDV) and enhances the PEDV infection (220).…”

“…The discovery of novel therapeutic options against important human and animal viral pathogens can be advanced by understanding how cellular RBPs, including hnRNPs, regulate virus infection (49). For example, in addition to acting as a host-protective mechanism, hnRNP A1 may also hold potential as an antiviral target to develop therapy for human rhinovirus (HRV) and IAV (157,158,219). Similarly, hnRNP E2 has the inhibitory effects on VSV replication (240).…”

hnRNPA1 impedes snakehead vesiculovirus replication via competitively disrupting viral phosphoprotein-nucleoprotein interaction and degrading viral phosphoprotein

“…hnRNPA1 binds with viral RNA and viral polymerase NS5B to inhibit hepatitis C virus replication [ 13 , 14 ]. Besides, hnRNPA1 interacts with NP of influenza A virus and inhibits viral replication [ 15 ]. On the other hand, it acts as a pro-viral factor.…”

Interaction of Influenza A Nucleoprotein with Host hnRNP-C Is Implicated in Viral Replication

“…hnRNP-C is implicated in numerous viral infections, including poliovirus, hepatitis delta virus, Ebola virus, dengue virus, the human papillomavirus type 16, MERS-CoV, and SARS-CoV-2 [ 16 , 17 , 18 , 19 , 20 ]. Recently, influenza NP was shown to interact with hnRNP-A2/B1, hnRNP-AB, and hnRNP-A1, which are also members of the family of more than 20 hnRNPs [ 21 , 22 , 23 ], while hnRNP-C was suggested to interact with influenza NS1 [ 24 ]. NP was found to interact with the glycine-rich domain of hnRNP-A2/B1, which was shown to be a positive regulator of RNP activity [ 21 ].…”

“…As such, viral replication is repressed. Kaur et al then demonstrated that hnRNP-A1 interacts with NP so that it negatively regulates the NP expression level and viral growth via an unknown pathway [ 23 ]. Hence, the binding of different hnRNPs to NP may lead to either up- or downregulation of RNP activity.…”