Cytosolic DNA-sensing immune response and viral infection

Abstract

How host cells recognize many kinds of RNA and DNA viruses and initiate innate antiviral responses against them has not yet been fully elucidated. Over the past decade, investigations into the mechanisms underlying these antiviral responses have focused extensively on immune surveillance sensors that recognize virus-derived components (such as lipids, sugars and nucleic acids). The findings of these studies have suggested that antiviral responses are mediated by cytosolic or intracellular compartment sensors and their adaptor molecules (e.g., TLR, myeloid differentiation primary response 88, retinoic acid inducible gene-I, IFN-β promoter stimulator-1, cyclic GMP-AMP synthase and stimulator of IFN genes axis) for the primary sensing of virus-derived nucleic acids, leading to production of type I IFNs, pro-inflammatory cytokines and chemokines by the host cells. Thus, host cells have evolved an elaborate host defense machinery to recognize and eliminate virus infections. In turn, to achieve sustained viral infection and induce pathogenesis, viruses have also evolved several counteracting strategies for achieving immune escape by targeting immune sensors, adaptor molecules, intracellular kinases and transcription factors. In this review, we discuss recent discoveries concerning the role of the cytosolic nucleic acid-sensing immune response in viral recognition and control of viral infection. In addition, we consider the regulatory machinery of the cytosolic nucleic acid-sensing immune response because these immune surveillance systems must be tightly regulated to prevent aberrant immune responses to self and non-self-nucleic acids.

Keywords: cyclic GMP-AMP synthase; interferon; stimulator of IFN genes; viral immune evasion.

Figure 1

Cytosolic DNA‐sensing immune response via cGAS/STING. A schematic of the cytosolic DNA‐sensing immune response via the cGAS/STING pathway. Upon DNA virus infection, the cytosolic DNA sensor cGAS directly recognizes viral DNA and catalyzes cGAMP, which utilizes cellular GTP/adenosine triphosphate, thereby triggering activation of the signal adaptor STING via direct interaction with cGAMP. cGAS may also recognize the transfected dsDNA or viral DNA that is produced by HIV‐1 through reverse‐transcription of viral RNA. Following the binding of cGAMP, STING is translocated from the ER to perinuclear‐Golgi and may form a signaling complex with kinase TBK1 (phosphorylation of STING at Serine[S]‐366 occurs here after translocation), thus inducing production of IRF3‐mediated type I IFNs. STING may also activate production of NF‐κB(p65)‐mediated pro‐inflammatory cytokines. cGAS may also recognize self‐DNAs, such as the released nucleosome and micronuclear DNA in the cytoplasm during DNA damage or cellular senescence, promoting STING‐dependent signal activation. Missense mutation of a number of cellular DNases may induce aberrant inflammatory responses via the cGAS/STING axis as a result of failure of self‐DNA digestion in necrotic or inappropriately apoptotic cells. P; phosphorylation

Figure 2

Viral strategies for evading the cGAS/STING pathway. Schema summarizing virus‐mediated immune strategies for evasion of the cGAS/STING pathway. To escape from the cytosolic DNA‐sensing immune response via the cGAS/STING pathway, several viruses may manipulate this signal activation through various evasion strategies, including: (i) inhibition of the function of cGAS or STING via physical interaction; (ii) manipulation of the PTMs system involved in the cGAS/STING function; (iii) induction of proteolysis and degradation of cGAS or STING; (iv) sequestration of the DNA‐sensing process mediated by cGAS; and (v) inhibition of STING‐dependent signal activation at the level of transcription factors such as IRF3 and NF‐κB. HcoV, human coronavirus; SARS, severe acute respiratory syndrome; PEDV, porcine epidemic diarrhea virus; HTLV‐1, human T lymphotropic virus type‐1; 63, K63‐linked ubiquitin.

Figure 3

Crosstalk between enveloped RNA virus infection and STING dependent signal activation. Schema showing the viral RNA‐sensing immune response via the cytosolic DNA‐sensing pathway. Upon RNA virus infection, RNA helicase RIG‐I directly recognizes viral RNA and activates IFN production through interaction with mitochondrial adaptor IPS‐1. (a) STING may also associate with signaling complex of RIG‐I and IPS‐1, promoting triggering of the antiviral response in cells upon RNA virus infection (23). (b) Enveloped RNA viruses such as IAV, NDV and Sendai virus activate IFN production through a viral envelope‐mediated fusion process in a STING‐dependent but cGAS‐independent manner; however, the molecular mechanism of signal transduction is yet to be clarified (97). As shown in Figure 2, the hemagglutinin fusion peptide of IAV may also associate with STING via its dimerization interphase domain, thereby inhibiting STING‐dependent signal activation. Abbreviations: FP, fusion peptide

Figure 4

A model of DENV‐mediated activation of the cytosolic DNA‐sensing pathway in DCs. Schema showing DENV‐mediated activation of the cytosolic DNA‐sensing pathway through induction of mitochondrial dysfunction. Upon DENV infection in DCs, RIG‐I directly recognizes viral RNA and activates IFN production through interaction with mitochondrial adaptor IPS‐1. DENV infection also triggers a mitochondrial damage response via induction of reactive oxygen species, resulting in mitochondrial DNA release in the cytoplasm that in turn stimulates signal activation via the cGAS/STING axis. As shown in Figure 2, DENV NS2B/NS3 protease and NS2B protease co‐factor alone may directly target STING and cGAS, thus suppressing their signal activation. Abbreviations: ROS, reactive oxygen species.