Post-transcriptional regulation of gene expression in innate immunity

• Published in: Nature reviews. Immunology Vol. 14; no. 6; pp. 361 - 376
• Main Authors: Carpenter, Susan, Ricci, Emiliano P., Mercier, Blandine C., Moore, Melissa J., Fitzgerald, Katherine A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2014; Nature Publishing Group
• Subjects: 3' Untranslated regions; 631/250/2502; Adaptive immunity; Adaptive Immunity - genetics; Alternative splicing; Alternative Splicing - genetics; Alternative Splicing - immunology; Animals; Biodegradation; Biomedicine; Decay; Dendritic Cells - immunology; Gene expression; Gene Expression Regulation - immunology; Gene regulation; Genetic aspects; Genetic research; Genetic transcription; Humans; Immune response; Immune system; Immunity; Immunity (Disease); Immunity, Innate - genetics; Immunological research; Immunology; Inflammation; Inflammation - genetics; Initiation factor eIF-2; Initiation factor eIF-4E; Innate immunity; Localization; Medical research; Mice; Microorganisms; MicroRNAs; miRNA; mRNA stability; mRNA turnover; Pathogens; Pattern recognition; Phosphorylation; Polyadenylation; Polyadenylation - genetics; Post-transcription; Protein Biosynthesis - genetics; Proteins; Proteomes; review-article; RNA Processing, Post-Transcriptional - immunology; RNA Stability - genetics; RNA Stability - immunology; RNA, Messenger - genetics; RNA, Untranslated - genetics; RNA, Untranslated - immunology; Signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; Toll-like receptors; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Transcription activation; Transcription factors; Translation elongation; γ-Interferon; United States > US; Massachusetts
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/nri3682

Key Points This Review summarizes post-transcriptional regulation in the innate immune response. We discuss the regulatory mechanisms that function at the level of mRNA splicing, mRNA polyadenylation, mRNA stability and protein translation, and outline how these mechanisms control the initiation, magnitude, duration and resolution of the inflammatory response. More than 94% of human genes are subject to alternative splicing or alternative polyadenylation. This provides diversity within the proteome of cells of the innate immune system. Alternative splicing can be activated following bacterial challenge as a defence mechanism, favouring proximal 3′ untranslated regions (3′ UTRs) and preventing mRNA degradation by microRNAs (miRNAs). Alternative polyadenylation can alter the UTRs, thus markedly affecting the localization and stability of mRNA. Activation of the Toll-like receptor (TLR) signalling pathway results in a complex signalling cascade that is controlled by numerous mechanisms. In this Review, we highlight the complex nature of alternative splicing and alternative polyadenylation, and how they affect nearly every protein within the TLR signalling cascade. Studies of total and nascent RNA transcripts following inflammatory activation reveal that the stimulated levels of transcripts are controlled by transcription. However, the duration of this response is subject to control by RNA decay. mRNA decay can occur through AU-rich element (ARE)-mediated, non-ARE-mediated or nonsense-mediated decay pathways. Importantly, these studies highlight that regulation of mRNA degradation is an essential step in shaping innate immune responses. Regulation of immune genes at the level of translation is essential as many proteins are required within minutes following stimulation. Eukaryotic translation initiation factor 2 (eIF2) and eIF4E are highly regulated by phosphorylation within the inflammatory signalling pathway to modulate translation. The concept of translation re-initiation seems to have widespread use within innate immune genes, where it allows for an increase in protein diversity without the requirement for alternative splicing. Translational regulation of genes involved in innate immunity is also mediated by the interferon-γ-activated inhibitor of translation (GAIT) complex and ARE-binding proteins, as well as through the control of translation elongation. Long non-coding RNAs are emerging as key regulators of innate immunity. To date, they have been implicated in the control of gene expression at the level of transcription. Their roles in post-transcriptional regulation have been described in other biological contexts; however, whether these functions are also involved in innate immunity remains to be determined. In this Review, the authors highlight the importance of the diverse mechanisms that regulate the expression of innate immune genes post transcription. These regulatory mechanisms act at the level of mRNA splicing, mRNA polyadenylation, mRNA stability and protein translation, and they are important for controlling the magnitude and duration of inflammatory responses. Innate immune responses combat infectious microorganisms by inducing inflammatory responses, antimicrobial pathways and adaptive immunity. Multiple genes within each of these functional categories are coordinately and temporally regulated in response to distinct external stimuli. The substantial potential of these responses to drive pathological inflammation and tissue damage highlights the need for rigorous control of these responses. Although transcriptional control of inflammatory gene expression has been studied extensively, the importance of post-transcriptional regulation of these processes is less well defined. In this Review, we discuss the regulatory mechanisms that occur at the level of mRNA splicing, mRNA polyadenylation, mRNA stability and protein translation, and that have instrumental roles in controlling both the magnitude and duration of the inflammatory response.