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Review
. 2019:344:1-30.
doi: 10.1016/bs.ircmb.2018.08.004. Epub 2018 Oct 26.

Discrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System

Takumi Kawasaki  1 , Taro Kawai  2
Affiliations
Review

Discrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System

Takumi Kawasaki et al. Int Rev Cell Mol Biol. 2019.

Abstract

During viral and bacterial infections, the innate immune system recognizes various types of pathogen-associated molecular patterns (PAMPs), such as nucleic acids, via a series of membrane-bound or cytosolic pattern-recognition receptors. These include Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), AIM2-like receptors (ALRs), and cytosolic DNA sensors. The binding of PAMPs to these receptors triggers the production of type I interferon (IFN) and inflammatory cytokines. Type I IFN induces the expression of interferon stimulated genes (ISGs), which protect surrounding cells from infection. Some ISGs are nucleic acids-binding proteins that bind viral nucleic acids and suppress their replication. As nucleic acids are essential components that store and transmit genetic information in every species, infectious pathogens have developed systems to escape from the host nucleic acid recognition system. Host cells also have their own nucleic acids that are frequently released to the extracellular milieu or the cytoplasm during cell death or stress responses, which, if able to bind pattern-recognition receptors, would induce autoimmunity and inflammation. Therefore, host cells have acquired mechanisms to protect themselves from contact with their own nucleic acids. In this review, we describe recent research progress into the nucleic acid recognition mechanism and the molecular bases of discrimination between self and non-self-nucleic acids.

Keywords: ISG; Innate immunity; Nucleic acid; Self and non-self; Type-I interferon.

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Figures

Fig. 1
Fig. 1
Recognition of nucleic acids by PRRs. TLR3, 7/8, 9 and 13 are localized in endosomes. TLR3 recognizes dsRNAs, TLR7/8 recognizes ssRNAs and guanosine derivatives such as R837 and R848, TLR9 recognizes dsDNAs, and TLR13 recognizes 23S rRNAs. Ligand binding TLRs associate with MyD88 and/or TRIF in the cytosol. Intracellular RNA is recognized by RIG-I and MDA5, which bind to short dsRNAs and long dsRNAs, respectively. The binding of RIG-I and MDA5 to nucleic acids induces the formation of filaments that bind to mitochondria-localizing IPS-1 (MAVS). Intracellular dsDNAs bind to cGAS and produce cGAMP. cGAMP binds to STING which localizes in the endoplasmic reticulum (ER). Activation of the MyD88/TRIF, IPS-1 and STING adaptor proteins induces translocation of the transcription factors NF-κB and IRF to the nucleus following the production of type I IFN and inflammatory cytokines. AIM2 and IFI16 bind to dsDNAs and form an inflammasome with ASC and caspase-1. Activation of caspase-1 cleaves pro-IL-1β or pro-IL-18 to the mature forms of IL-1β and IL-18, respectively.
Fig. 2
Fig. 2
Regulation of nucleic acid-related restriction by ISGs. Released type I IFNs induce various types of ISGs expression in surrounding cells. ISG expression protects cells from viral and bacterial infections. RIG-I and MDA5 work as a receptor and a viral restriction factor by binding to short dsRNAs and long dsRNAs, respectively. PKR binds to RNAs that have bulges and internal loops, MOV10 binds to dsRNAs, and IFIT1 binds to ssRNAs. OAS binds to dsRNAs and generates 2′-5′A to activate RNase L. APOBEC3 catalyzes the deamination of cytidine (C) to uridine (U) in ssDNA substrates. ADAR catalyzes the conversion of adenosine (A) to inosine (I) in dsRNA substrates. SAMHD1 is a triphosphohydrolase that converts deoxynucleoside triphosphates to deoxynucleoside and triphosphate, which reduces cellular dNTP levels. TREX1 (DNase III) degrades dsDNAs in extracellular spaces, and DNase II degrades endosomal dsDNAs derived from the macrophage engulfment of dead cells.
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