The innate immune system utilizes pattern-recognition receptors (PRRs) to detect the invasion of pathogens and initiate host antimicrobial responses such as the production of type I interferons and proinflammatory cytokines. Nucleic acids, which are essential genetic information carriers for all living organisms including viral, bacterial, and eukaryotic pathogens, are major structures detected by the innate immune system. However, inappropriate detection of self nucleic acids can result in autoimmune diseases. PRRs that recognize nucleic acids in cells include several endosomal members of the Toll-like receptor family and several cytosolic sensors for DNA and RNA. Here, we review the recent advances in understanding the mechanism of nucleic acid sensing and signaling in the cytosol of mammalian cells as well as the emerging role of cytosolic nucleic acids in autoimmunity.

Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids

Cytosolic Sensing of Viruses

Over the past few years, several groups have identified new genes that are transcriptionally induced downstream of type I interferon (IFN) signalling and that inhibit infection by individual or multiple families of viruses. Among these IFN-stimulated genes with antiviral activity are two genetically and functionally distinct families--the IFN-induced protein with tetratricopeptide repeats (IFIT) family and the IFN-induced transmembrane protein (IFITM) family. This Review focuses on recent advances in identifying the unique mechanisms of action of IFIT and IFITM proteins, which explain their broad-spectrum activity against the replication, spread and pathogenesis of a range of human viruses.

The broad-spectrum antiviral functions of IFIT and IFITM proteins

Intrinsic antiviral immunity refers to a form of innate immunity that directly restricts viral replication and assembly, thereby rendering a cell nonpermissive to a specific class or species of viruses. Intrinsic immunity is conferred by restriction factors that are mostly preexistent in certain cell types, although these factors can be further induced by viral infection. Intrinsic virus-restriction factors recognize specific viral components, but unlike other pattern-recognition receptors that inhibit viral infection indirectly by inducing interferons and other antiviral molecules, intrinsic antiviral factors block viral replication immediately and directly. This review focuses on recent advances in understanding of the roles of intrinsic antiviral factors that restrict infection by human immunodeficiency virus and influenza virus.

/pdf/intrinsic-antiviral-immunity-673qxy7f96.pdf

Intrinsic antiviral immunity

https://www.cell.com/immunity/pdf/S1074-7613(16)30242-4.pdf

Post-Translational Modification Control of Innate Immunity

IFN-stimulated gene 56 (ISG56) is one of the first identified proteins induced by viruses and type I IFNs. In this study, we identified ISG56 as a virus-induced protein associated with MITA, an adapter protein involved in virus-triggered induction of type I IFNs. Overexpression of ISG56 inhibited Sendai virus-triggered activation of IRF3, NF-κB, and the IFN-β promoter, whereas knockdown of ISG56 had opposite effects. Consistently, overexpression of ISG56 reversed cytoplasmic poly(I:C)-induced inhibition of vesicular stomatitis virus (VSV) replication, whereas knockdown of ISG56 inhibited VSV replication. Competitive coimmunoprecipitation experiments indicated that ISG56 disrupted the interactions between MITA and VISA or TBK1, two components in the virus-triggered IFN signaling pathways. These results suggest that ISG56 is a mediator of negative-feedback regulation of virus-triggered induction of type I IFNs and cellular antiviral responses.

https://www.pnas.org/content/pnas/106/19/7945.full.pdf

ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response

Detection of viral nucleic acids by pattern recognition receptors initiates type I interferon (IFN) induction and innate antiviral response. The RIG-I-like receptors (RLRs), including RIG-I and MDA5, recognize cytoplasmic viral RNA in most cell types and are critically involved in innate antiviral response. RIG-I and MDA5 are structurally related and mediate similar signaling pathways. While the regulation of RIG-I activity has been extensively investigated, little is known about the regulatory mechanisms of MDA5 activity. Here we identified ribonucleoprotein PTB-binding 1 (RAVER1) as a specific MDA5-interacting protein. RAVER1 was associated with MDA5 upon viral infection. Overexpression of RAVER1 at low dosages enhanced MDA5- but not RIG-I-mediated activation of the IFN-β promoter, whereas knockdown of RAVER1 inhibited MDA5- but not RIG-I-mediated induction of downstream antiviral genes. Mechanistically, overexpression of RAVER1 enhanced the binding of MDA5 to its ligand poly(I:C), whereas knockdown of RAVER1 had opposite effect. Our findings suggest that RAVER1 specifically regulates MDA5 activity, revealing a mechanism of differential regulation of MDA5- and RIG-I-mediated innate antiviral response.

RAVER1 is a coactivator of MDA5-mediated cellular antiviral response

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ISG56 is a negative-feedback regulator of virus-triggered signaling and cellular antiviral response

RAVER1 is a coactivator of MDA5-mediated cellular antiviral response