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The multifarious roles of heterogeneous ribonucleoprotein A1 in viral infections

Summary Viruses are obligate parasites known to interact with a wide variety of host proteins at different stages of infection. Current antiviral treatments target viral proteins and may be compromised due to the emergence of drug resistant viral strains. Targeting viral‐host interactions is now gaining recognition as an alternative approach against viral infections. Recent research has revealed that heterogeneous ribonucleoprotein A1, an RNA‐binding protein, plays an essential functional and regulatory role in the life cycle of many viruses. In this review, we summarize the interactions between heterogeneous ribonucleoprotein A1 (hnRNPA1) and multiple viral proteins during the life cycle of RNA and DNA viruses. hnRNPA1 protein levels are modulated differently, in different viruses, which further dictates its stability, function, and intracellular localization. Multiple reports have emphasized that in Sindbis virus, enteroviruses, porcine endemic diarrhea virus, and rhinovirus infection, hnRNPA1 enhances viral replication and survival. However, in others like hepatitis C virus and human T‐cell lymphotropic virus, it exerts a protective response. The involvement of hnRNPA1 in viral infections highlights its importance as a central regulator of host and viral gene expression. Understanding the nature of these interactions will increase our understanding of specific viral infections and pathogenesis and eventually aid in the development of novel and robust antiviral intervention strategies.

Recent technical advances in methodology, including genomewide RNA interference (RNAi) screens, yeast two-hybrid (Y2H) screens, and transcriptional gene expression profiling, have identified hundreds of host proteins involved in viral infections, of which about one in five are RNA-binding proteins (RBPs). [11][12][13][14][15] The multifaceted role of the host RNA machinery means that RBPs are at the center of host-virus cross-talk. However, a comprehensive understanding of the sizeable network of host proteins interacting with the viral machinery still remains to be elucidated.
The transcripts of protein-coding genes in the nucleus of eukaryotic cells are known as heterogeneous nuclear RNAs (hnRNAs). After being transcribed, cellular pre-mRNAs associate with nuclear proteins to form heterogeneous nuclear ribonucleoprotein (hnRNP) complexes, which function to affect the structure, posttranscriptional processing, or nucleocytoplasmic transport of these mRNAs. 16,17 They also regulate splicing, nuclear export of mRNAs, telomere biogenesis, DNA repair, transcription, translation, and cell signalling. [17][18][19] The hnRNP family comprises of more than 20 evolutionarily conserved proteins, named alphabetically from hnRNPA1-hnRNPU in humans. 17 All the members of the family share a common modular structure consisting of one or more RNA-binding domains (RBDs) which dictate their interaction with RNA. 17 hnRNPA1 is the most abundant RBP in the hnRNP(A/B) subfamily. It affects the expression of many critical genes in the host, at the transcriptional, posttranscriptional, translational, and posttranslational level which are responsible for controlling crucial metabolic pathways in the host. [19][20][21][22] The N-terminal domain of the protein encodes two RBDs which are pivotal for RNA specificity and binding ( Figure 1). Additionally, a flexible glycine-rich arginine-glycine-glycine (RGG) region known as the RGG box imparts protein and RNA binding features to the protein. Downstream of the RGG box, there is a 38 amino acid (aa) sequence termed the M9 nuclear localisation sequence (NLS) in the glycine (Glyc) rich region, which facilitates bidirectional nucleo-cytoplasmic shuttling of the protein by means of its interaction with the members of importin α/β sub-family 17,[23][24][25] ( Figure 1). Transportin-1 interacts with the Glyc-rich region (195-268 aa) of hnRNPA1 by the virtue of its F-peptide (301-318 aa). 25 Post-translation modifications (PTMs) in a protein are known to affect their activity and binding affinity. Likewise, several posttranslational modifications like phosphorylation, methylation, ubiquitination, and sumoylation dictate the activity and compartmentalization of hnRNPA1 in a cell. 17 For instance, methylation of arginine residues in the RGG motif may regulate the RNA-binding activity of the protein. 21,[26][27][28] Similarly, kinases such as protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and ribosomal S6 kinases (S6Ks) phosphorylate serine residues present at both the N and C terminal of the protein, regulating its function. 17,21,[29][30][31] PTMs like phosphorylation in the C-terminal region of the protein result in cytoplasmic accumulation of hnRNPA1. 22,25,30 Contrastingly, the addition of O-GlcNAcylation (GlcNAc) moiety to the serine or threonine aa via β-O-linkage is a commonly occurring, reversible modification which impairs the binding of hnRNPA1 to karyopherin β (Transportin-1). 25,32 This leads to enhanced nuclear localization of the protein, eventually affecting its activity. 25

| MULTIPLE ROLES OF HNRNPA1 IN VIRUSES
Based on the polarity of the genome, viruses are categorized as positive sense or negative sense. Depending on their genetic makeup, they need to utilize many RBPs to successfully complete their infection cycle in the host. [33][34][35] As the replication of the viral genome takes place in the host cytoplasm or nucleus, they must have a mechanism in place to discriminate between the cellular and viral RNAs present in an infected cell. Moreover, due to their limited coding capacity, they F I G U R E 1 Structural and functional features of heterogeneous ribonucleoprotein (hnRNPA1). hnRNPA1 has two different isoforms (A1-A, 372 AMino acids; A1-B, 320 AMino acids). N-terminal domain imparts the RNA recognition and specificity to the protein by RNA recognition motifs (RRM 1, RRM 2) while C terminal domain comprises of arginine-glycine-glycine (RGG) region and M9; nuclear localisation sequence (NLS) that dictates the sub-cellular localisation of the protein lack preexisting RNA machinery to ensure successful replication in the host. Owing to all these factors, viruses have strategically evolved to exploit host RNA-binding proteome and evade host RNA degradation mechanisms. hnRNPA1 is an RBP involved at multiple stages postinfection that, depending on the virus in question, has contradictory roles; in some, it promotes viral replication, while in others, it abrogates it. Diverse roles exhibited by the protein are summarized below (Tables 1-4).

| Antiviral role of hnRNPA1
By the virtue of advanced techniques like RNAi screen, microarray, forward chemical genetics, proteomic, Y2H screens, and RNA immu- were observed after hnRNPA1 silencing. 60 The authors speculate that since hnRNPA1 binds to both the CRE and viral polymerase, it might compete with the latter, for efficient viral replication thereby exerting an antiviral effect. 60 Viruses in which hnRNPA1 plays an antiviral role are summarized below (Table 1).

| Pro-viral role of hnRNPA1
Pro-viral effect was seen in Sindbis virus infection model, wherein  39 Combined knockdown of hnRNPA1 and hnRNPA2B1 greatly impaired viral RNA translation, impeding viral replication. 70,71 Biophysical studies also showed that the SL-II domain undergoes a conformational change to assemble a viable hnRNPA1-RNA complex.
Mutations or deletions in this region completely impair viral replication. 39 Cammas et al reported physical binding of hnRNPA1 to the 5 0 UTR region of human rhinovirus (HRV) IRES. 40   Hepatitis C virus (HCV) 24 whereas mutant hnRNPA1 1-184 (1-184 aa) lost its capacity to interact with p17, thereby leading to the nuclear accumulation of ARV p17 protein. 42 Multiple reports suggest that ARV p17 protein induces autophagy that is mandatory to support efficient replication in the host. [74][75][76] The authors suggest that ARV p17-hnRNPA1 interaction is needed for import and export of the p-17 cargo via the nuclear pore complex (NPC). Additionally, siRNA-mediated knockdown of hnRNPA1 in p17 transfected Vero cells exhibited nuclear retention of p17, 17 to 30 hours posttransfection. 42 Furthermore, siRNA-mediated depletion of hnRNPA1 in Vero cells dropped ARV titer, establishing that hnRNPA1 plays a pro-viral role in ARV infection. 42 Various viruses in which hnRNPA1 supports viral replication in the host are listed in Table 2.

| Controversial role of hnRNPA1
In the case of human immunodeficiency virus 1 (HIV-1) infection, con-

| Undesignated role for hnRNPA1
In Epstein-Barr virus (EBV) infection, hnRNPA1 has been speculated to regulate the splicing of latent membrane protein 2 (LMP-2) mRNA by its interaction with the intronic region in the LMP2 mRNA in association with hnRNPU and beta actin. 52 In silico prediction studies

| CONCLUSION AND FUTURE DIRECTIONS
Viruses are known to usurp many host cell proteins for their own benefit. 1  RBPs have been established as cis-and trans-acting elements, hnRNPA1 acts as a cis-acting element in SARS CoV infection model, controlling viral gene expression. 81 It also binds SARS nucleocapsid protein, facilitating the binding of other cis-or trans-activating factors, to ensure viral transcription and replication. 81 In MHV infection, hnRNPA1 binds to positive and negative viral RNA. [82][83][84] However, the role of hnRNPA1 in MHV infection is controversial. Viral replication was enhanced post-hnRNPA1 transfection, but in hnRNPA1 silenced cell lines, no retardation in viral replication was observed, 49,83,87,88 indicating that the effect incurred may be substituted by other isoforms or members of hnRNP family.
In EBV and HPV-16 infections, although hnRNPA1 has been reported to bind to viral RNA, 52,94,[97][98][99] further studies directed towards how these interactions dictate virus survival need further investigation. Likewise, in VSV infection, hnRNPA1 was not seen to directly affect viral replication but hnRNPA1 silenced cells displayed delayed onset of virus induced apoptotic events. 54 The varied profile of hnRNPA1 in multiple viruses may also appertain to the diverse replication profile exhibited by these viruses. Similar alterations in related viruses may elicit different consequences for viral replication.
Although all these observations are fascinating, many questions pertaining to the functional implication of hnRNPA1 in the host, postviral infections, still remain unsolved. Unravelling the complexity and the fate of these hnRNPA1-virus interactions not only enhances our current understanding of the disease biology and pathogenesis but also helps identify crucial nodal points which can be exploited further.
Additionally, it will be imperative to utilize the interactions between viral proteins and hnRNPA1 as tools to identify biomarkers for diagnostic measures and host-based therapeutics.

CONFLICT OF INTERESTS
The authors declare no conflict of interests.