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Interplay between RNA viruses and cGAS/STING axis in innate immunity - PubMed

  • ️Sun Jan 01 2023

Review

Interplay between RNA viruses and cGAS/STING axis in innate immunity

Lucia Amurri et al. Front Cell Infect Microbiol. 2023.

Abstract

While the function of cGAS/STING signalling axis in the innate immune response to DNA viruses is well deciphered, increasing evidence demonstrates its significant contribution in the control of RNA virus infections. After the first evidence of cGAS/STING antagonism by flaviviruses, STING activation has been detected following infection by various enveloped RNA viruses. It has been discovered that numerous viral families have implemented advanced strategies to antagonize STING pathway through their evolutionary path. This review summarizes the characterized cGAS/STING escape strategies to date, together with the proposed mechanisms of STING signalling activation perpetrated by RNA viruses and discusses possible therapeutic approaches. Further studies regarding the interaction between RNA viruses and cGAS/STING-mediated immunity could lead to major discoveries important for the understanding of immunopathogenesis and for the treatment of RNA viral infections.

Keywords: RNA virus; antiviral strategies; cGAS/STING; host-pathogen interactions; innate immunity; viral evasion.

Copyright © 2023 Amurri, Horvat and Iampietro.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1

STING signalling pathways. Diverse stimuli (in red), including infections by DNA virus, bacteria or protozoa, mitochondrial membrane disruption, possible Mn2+ release, extracellular cGAMP import and neutrophil extracellular traps (NETs) generation trigger the release of intracellular DNA in the cytoplasm. Moreover, double strand breaks (DSB) in genomic DNA, occurring during cancer, senescence, autoimmune disorders, UV exposure and membrane fusion, contribute to the liberation of self-DNA in cytosol and to the dissociation of cGAS and IFI16 (in yellow) from intact chromatin. Both cGAS and IFI16 detect cytoplasmic DNA (in purple). However, while cGAS activates STING by synthesizing its agonist 2’3’-cGAMP, IFI16 elicits STING activation through a non-canonical mechanism in complex with p53 and TRAF6. Once activated, STING oligomerizes and translocates to Golgi apparatus, where it undergoes phosphorylation and ubiquitination. Consequently, it stimulates the nuclear translocation of IRF-3 and NF-kB transcription factors and further expression of IFN I and inflammatory cytokines, leading to the activation of JAK/STAT signaling pathway in autocrine and paracrine manner.

Figure 2
Figure 2

Canonical RNA- and DNA-sensing pathways. Following viral penetration into target cells, viral nucleic acids are recognized by cellular PRRs specialized in the detection of specific RNA and DNA species. RNA-sensing pathways (in green) are mediated by TLRs (A) and RLRs (B) and can sense different types of virus-derived RNA in endosomes or cytoplasm, respectively. (C) cGAS/STING is the major cytoplasmic DNA-sensing axis (in blue) and it plays an essential role as primary player in the canonical response to DNA virus infections. According to each receptor activation, different adaptor molecules are recruited, leading to the formation of four separate innate immune axes: TRL3/TRIF, TLR7/8/MyD88, RLRs/MAVS and cGAS/STING. Nonetheless, all these pathways converge in an unique cascade with the activation of TBK1/IRF3/7 and IKK/NF-kB, ultimately resulting in the activation of IFN response and cytokines production. Moreover, the four axes can cross-talk at different levels both directly and indirectly, leading to a complex network of interactions between the effectors of innate immune response.

Figure 3
Figure 3

Mechanism of indirect cGAS/STING activation by RNA virus infection and STING-mediated control of RNA viral evasion. RNA virus infections trigger the release of self dsDNA in the cytoplasm due to mitochondrial stress (1) and/or genomic DNA damage and micronuclei formation (2) (red). Double strand breaks (DSB) and micronuclei can also be induced by virus-induced cell-to-cell fusion (syncytia formation, in red) (3). Cytoplasmic DNA is then detected by cGAS and IFI16 sensors leading to STING activation. Moreover, STING can be activated non-canonically by nuclear matrix protein scaffold attachment factor A (SAFA) through the mediation of viral RNA during Bunyaviridae infections (4). Finally, while IFN induction is considered the major STING-dependent anti-viral mechanism, STING and cGAS can also limit vesicular stomatitis virus (VSV) infection by inhibiting protein translation and by enhancing IFN expression through Prmt5 activation, respectively (5). DENV, Dengue virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; IAV, influenza A virus; ECMV, encephalomyocarditis virus; MeV, measles virus; MNV, murine norovirus; SFTSV, severe fever with thrombocytopenia syndrome virus; m, methyl group.

Figure 4
Figure 4

Summary of the known mechanisms of cGAS/STING antagonism by RNA viruses as described in ( Table 1 ). Viral evasion strategies targeting STING (A), cGAS (B), mitochondrial DNA (C) or STING-dependent downstream signaling (D).

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The work was supported by Aviesan Sino-French agreement on Nipah virus study.