Viral Hijacking of Host Polyadenylation Machinery to Regulate Post-Transcriptional Gene Expression

Viruses have developed a diverse array of mechanisms to hijack host transcriptional machinery and ensure successful viral gene expression. One such method is through manipulation of the cellular machinery required for post-transcriptional processing of host messenger RNAs (mRNAs). 3’ end processing of host mRNA requires a complex suite of proteins that function together to identify potential polyadenylation sites, cleave the pre-mRNA at the selected site, and synthesize the polyadenosine tail. Under certain cellular conditions - including stress, disease, and infection - altered regulation of these complexes can lead to changes in alternative polyadenylation (APA) site usage, resulting in changes in 3’ untranslated region (UTR) length, transcript abundance, and translation potential. Recent studies have identified APA as an emerging regulator of viral infection. Viruses interact with polyadenylation machinery both directly and indirectly to facilitate viral gene expression, evade innate immune responses, and achieve targeted host shutoff. While the specific interactions vary, viral manipulation of 3’ post-transcriptional processing proteins is common among a range of viruses, including herpes simplex virus (HSV), influenza A virus (IAV), and human immunodeficiency virus (HIV). In this review, we provide an overview of cellular polyadenylation machinery and mechanisms of APA that are exploited by viruses, as well as the methods that can be used to analyze changes in APA. We highlight the ways in which a range of both DNA and RNA viruses manipulate post-transcriptional processing and APA to regulate viral and host gene expression and enhance cellular permissivity to infection. Finally, we highlight current knowledge gaps and future directions exploring the translatability of these discoveries toward the development of future therapeutic strategies.