The role of alternative polyadenylation in the antiviral innate immune response

Abstract

Alternative polyadenylation (APA) is an important regulatory mechanism of gene functions in many biological processes. However, the extent of 3′ UTR variation and the function of APA during the innate antiviral immune response are unclear. Here, we show genome-wide poly(A) sites switch and average 3′ UTR length shortens gradually in response to vesicular stomatitis virus (VSV) infection in macrophages. Genes with APA and mRNA abundance change are enriched in immune-related categories such as the Toll-like receptor, RIG-I-like receptor, JAK-STAT and apoptosis-related signalling pathways. The expression of 3′ processing factors is down-regulated upon VSV infection. When the core 3′ processing factors are knocked down, viral replication is affected. Thus, our study reports the annotation of genes with APA in antiviral immunity and highlights the roles of 3′ processing factors on 3′ UTR variation upon viral infection.

Posttranscriptional Regulation of HLA-A Protein Expression by Alternative Polyadenylation Signals Involving the RNA-Binding Protein Syncrip

“…Several studies indicate coupling of APA regulation with transcription(55–57), which may be related to the relative increase in short 3’UTRs across the transcriptome observed upon immune cell activation(58). Recently, vesicular stomatitis virus infection was shown to induce shortening of 3’UTRs globally and especially in immune genes (59). The global shortening of 3’UTRs is believed to facilitate rapid change in protein expression as well as increase in proliferation.…”

What Are 3′ UTRs Doing?

“…In addition to being cell type-specific, alternative 3 ′ UTR isoform expression responds to receptor stimulation and subsequent activation of signaling pathways as was shown during immune cell stimulation or synaptic activation. A change in 3 ′ UTR isoform ratio can be achieved through exposure of the cells to extracellular stimuli and can be mimicked experimentally by the addition of growth factors, cytokines, or neurotransmitters (Flavell et al 2008;Sandberg et al 2008;Rhinn et al 2012;Gruber et al 2014;Jia et al 2017). Expression ratios of alternative 3 ′ UTRs also change during normal development and differentiation (Lackford et al 2014;Brumbaugh et al 2018;Freimer et al 2018) as well as in disease (Mayr and Bartel 2009;Rhinn et al 2012;Batra et al 2014;Masamha et al 2014).…”

Re-evaluating Strategies to Define the Immunoregulatory Roles of miRNAs

“…The regulatory mechanisms that control APA and the potential consequences to gene expression have been previously reviewed [53]. Acute viral infection of macrophages [54] and T cell activation [55] result in the global shortening in the 3′UTR of immune genes, resulting in the exclusion of MREs found the distal 3′UTR. Thus, in this context, miRNA-regulated gene expression is dependent on both changes in miRNA concentration and PAS utilization.…”

“…Utilizing such tools in the context of immune cell development or immune stimulus could further refine our understanding of both the importance of previously observed APA events (e.g. during immune cell development, differentiation, and activation [49, 50, 54, 62, 63]) and also allow us explore the involvement of miRNA-dependent regulation in these processes.…”