Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference.

/pdf/a-to-i-editing-of-coding-and-non-coding-rnas-by-adars-1r7hnvg690.pdf

A-to-I editing of coding and non-coding RNAs by ADARs

This Review describes the type I interferonopathies — a set of Mendelian disorders associated with the upregulation of type I interferon activity. The authors explain how defects in key components of innate immune signalling pathways can lead to these diseases and discuss the immunological insights that have resulted from their study.

Aicardi–Goutières syndrome and the type I interferonopathies

Host defence peptides (HDPs) are short, cationic amphipathic peptides with diverse sequences that are produced by various cells and tissues in all complex life forms. HDPs have important roles in the body's response to infection and inflammation. This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) of HDPs on the host. Studies have demonstrated that HDPs are expressed throughout the body and mediate a broad range of activities, which explains their association with various inflammatory diseases and autoimmune disorders. The diverse actions of HDPs, such as their roles in wound healing and in the maintenance of the microbiota, are also explored, in addition to potential therapeutic applications.

The immunology of host defence peptides: beyond antimicrobial activity

Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally occurring peptides that can combat infections through their direct microbicidal properties and/or by influencing the host's immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been used to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies.

/pdf/antimicrobial-host-defence-peptides-functions-and-clinical-48oa63nlrk.pdf

Antimicrobial host defence peptides: functions and clinical potential

Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) enzymes. In addition to RNA editing, additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1, we generated mice with an editing-deficient knock-in mutation (Adar1E861A, where E861A denotes Glu861→Ala861). Adar1E861A/E861A embryos died at ~E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)–sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3′ untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of Adar1E861A/E861A were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts.

http://science.sciencemag.org/content/sci/349/6252/1115.full.pdf

RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself

https://www.pure.ed.ac.uk/ws/files/17832252/The_RNA_Editing_Enzyme_ADAR1_Controls_Innate_Immune_Responses_to_RNA.pdf

The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA

β-Defensins are cationic host defense peptides that form an amphipathic structure stabilized by three intramolecular disulfide bonds. They are key players in innate and adaptive immunity and have recently been shown to limit the production of pro-inflammatory cytokines in TLR4-stimulated macrophages. In the present study, we investigate the mechanism underlying the anti-inflammatory effect of human β-defensin 3 (hBD3). We show that the canonical structure of hBD3 is required for this immunosuppressive effect and that hBD3 rapidly associates with and enters macrophages. Examination of the global effect of hBD3 on transcription in TLR4-stimulated macrophages shows that hBD3 inhibits the transcription of pro-inflammatory genes. Among the altered genes there is significant enrichment of groups involved in the positive regulation of NF-κB including components of Toll-like receptor signaling pathways. We confirm these observations by showing corresponding decreases in protein levels of pro-inflammatory cytokines and cell surface molecules. In addition, we show that hBD3 reduces NF-κB signaling in cells transfected with MyD88 or TRIF and that hBD3 inhibits the TLR4 response in both MyD88- and TRIF-deficient macrophages. Taken together these findings suggest that the mechanism of hBD3 anti-inflammatory activity involves specific targeting of TLR signaling pathways resulting in transcriptional repression of pro-inflammatory genes.

/pdf/human-b-defensin-3-affects-the-activity-of-pro-inflammatory-9yttlt0rho.pdf

Human β‐defensin 3 affects the activity of pro‐inflammatory pathways associated with MyD88 and TRIF

Antimicrobial peptides (also known as host defence peptides) are an increasingly well-characterized, central component of host defence against infection. These peptides are an ancient form of innate immunity, conserved across evolution; found in animals, plants and even produced by microorganisms themselves. As antibiotic resistance becomes an ever-greater concern for our ability to treat infectious diseases, the study of antimicrobial peptides is providing new insights into the functioning of innate immunity and providing templates for the development of novel therapeutics. As knowledge of the properties of these peptides has developed, it has also become clear that, in addition to broad-spectrum direct microbicidal potential, they have modulatory effects on innate and adaptive immune processes in mammals, as well as some apparently non-immune functions. This chapter focuses on two families of mammalian peptides; the defensins and the cathelicidins, concentrating primarily on human peptides, but with reference to homologous peptides in mouse models.

Sarah L. Cox

Papers

The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA

Human β‐defensin 3 affects the activity of pro‐inflammatory pathways associated with MyD88 and TRIF

Mammalian Antimicrobial Peptides; Defensins and Cathelicidins

Molecular Medical Microbiology - 2nd edition