Mechanism and consequences of herpes simplex virus 1-mediated regulation of host mRNA alternative polyadenylation

Abstract

Eukaryotic gene expression is extensively regulated by cellular stress and pathogen infections. We have previously shown that herpes simplex virus 1 (HSV-1) and several cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes and that the viral immediate early factor ICP27 plays an important role in HSV-1-induced DoTT. Here, we show that HSV-1 infection also leads to widespread changes in alternative polyadenylation (APA) of host mRNAs. In the majority of cases, polyadenylation shifts to upstream poly(A) sites (PAS), including many intronic PAS. Mechanistically, ICP27 contributes to HSV-1-mediated APA regulation. HSV-1- and ICP27-induced activation of intronic PAS is sequence-dependent and does not involve general inhibition of U1 snRNP. HSV1-induced intronic polyadenylation is accompanied by early termination of RNAPII. Finally, HSV-1-induced mRNAs polyadenylated at intronic PAS are exported into the cytoplasm while APA isoforms with extended 3’ UTRs are sequestered in the nuclei, both preventing the expression of the full-length gene products. Together with other recent studies, our results suggest that viral infection and cellular stresses induce a multi-faceted host shutoff response that includes DoTT and changes in APA profiles.

Emerging roles of alternative cleavage and polyadenylation (APA) in human disease

“…The HSV‐1 mRNAs with polyadenylation and with longer 3′‐UTR can both prevent the expressions of the host cell proteins and changes in these protein expressions might provide a suitable niche for the viral life cycle. Notably, HSV‐1 induces mRNA polyadenylation at the intronic PAS site, targets them to cytoplasm while mRNA with long 3′‐UTR localized within nuclei, thereby preventing the expression of host cells favoring viral life cycle (X. Wang, Liu, Whisnant, et al, 2020). Similarly, modulation of the host cell response in favor of bacterial infections was also identified during Salmonella enterica Typhimurium ( S. enterica Typhimurium) and was mediated by APA (Afonso‐Grunz, 2015).…”

“…APA perturbations can influence the polyadenylation site selection in pre‐mRNA, which, in turn, alters the mRNA size (Rehfeld et al, 2013). Changes in the mRNA size can affect several biological processes and play a role in developing heart, cancer, endocrine, hematological, infectious, and neurological disease (Jia et al, 2017; Masamha et al, 2014; Nimura et al, 2016; Shu et al, 2009; X. Wang, Liu, Whisnant, et al, 2020). APA often occurs along with splicing and thus causes abnormal posttranscriptional regulation (Grassi et al, 2019).…”

The Herpes Simplex Virus 1 Protein ICP4 Acts as both an Activator and a Repressor of Host Genome Transcription during Infection

“…Consistent with decreased levels of host genome transcription, studies have shown there is a widespread reduction of Pol II occupancy on the host genome within hours after HSV-1 infection [12]. Studies have also implicated several IE viral proteins in influencing or associating with Pol II or its general transcription factors [13][14][15][16][17], although the impact on host transcriptional activity is not clear. A recent study identified the IE protein infected cell polypeptide 4 (ICP4) as a major regulator of Pol II occupancy at host promoters facilitating the transcriptional switch from the host genome to the viral genome [18].…”

“…A recent study identified the IE protein infected cell polypeptide 4 (ICP4) as a major regulator of Pol II occupancy at host promoters facilitating the transcriptional switch from the host genome to the viral genome [18]. Recent studies have also shown that ICP27 is important for regulating transcription termination by Pol II at host genes [13,17]. Much remains to be learned about the interplay between host and viral factors in regulation of Pol II activity during infection.…”

HSV-1 and influenza infection induce linear and circular splicing of the long NEAT1 isoform

“…The HSV-1 immediate-early proteins ICP27 and ICP22 are both known to interact with the host transcription and RNA processing machinery. ICP27 regulates splicing and polyadenylation by interacting with splicing factors and the mRNA 3' processing factor CPSF [29][30][31][32]. We recently demonstrated that ICP27 is sufficient but not necessary for disruption of transcription termination in HSV-1 infection [31].…”