Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING

Wu, Xiaomei; Wu, Fei-Hua; Wang, Xiaoqiang; Wang, Lilin; Siedow, James N.; Zhang, Weiguo; Pei, Zhen-Ming

doi:10.1093/nar/gku569

Cited by 164 publications

(204 citation statements)

References 82 publications

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“…Quite surprisingly, the STING homologs found in mussel have a peculiar domain organization which is not found in other invertebrate genomes [134]. Like in insects, the deduced mussel STING proteins lack the N-terminal transmembrane domains anchoring vertebrate STING globular domain to the endoplasmic reticulum membrane, suggesting a different subcellular localization compared to vertebrates.…”

Section: Nod-like Receptors (Nlrs)mentioning

confidence: 85%

“…The STING protein is evolutionarily conserved, as its origins can be traced back to Choanoflagellates, even though it was lost during metazoan evolution in nematodes and flatworms [134]. While no sequence records are available for this protein in molluscs, we ascertained the presence of at least two full-length STING-like proteins in M. galloprovincialis and estimated the presence of 5 genes in the C. gigas genome.…”

Section: Nod-like Receptors (Nlrs)mentioning

confidence: 99%

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An updated molecular basis for mussel immunity

Gerdol

Venier

2015

Fish & Shellfish Immunology

134

163

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Non-self recognition with the consequent tolerance or immune reaction is a crucial process to succeed as living organisms. At the same time the interactions between host species and their microbiome, including potential pathogens and parasites, significantly contribute to animal life diversity. Marine filter-feeding bivalves, mussels in particular, can survive also in heavily anthropized coastal waters despite being constantly surrounded by microorganisms. Based on the first outline of the Mytilus galloprovincialis immunome dated 2011, the continuously growing transcript data and the recent release of a draft mussel genome, we explored the available sequence data and scientific literature to reinforce our knowledge on the main gene-encoded elements of the mussel immune responses, from the pathogen recognition to its clearance. We carefully investigated molecules specialized in the sensing and targeting of potential aggressors, expected to show greater molecular diversification, and outlined, whenever relevant, the interconnected cascades of the intracellular signal transduction. Aiming to explore the diversity of extracellular, membrane-bound and intracellular pattern recognition receptors in mussel, we updated a highly complex immune system, comprising molecules which are described here in detail for the first time (e.g. NOD-like receptors) or which had only been partially characterized in bivalves (e.g. RIG-like receptors). Overall, our comparative sequence analysis supported the identification of over 70 novel full-length immunity-related transcripts in M. galloprovincialis. Nevertheless, the multiplicity of gene functions relevant to immunity, the involvement of part of them in other vital processes, and also the lack of a refined mussel genome make this work still not-exhaustive and support the development of more specific studies.

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Section: Nod-like Receptors (Nlrs)mentioning

confidence: 85%

Section: Nod-like Receptors (Nlrs)mentioning

confidence: 99%

An updated molecular basis for mussel immunity

Gerdol

Venier

2015

Fish & Shellfish Immunology

134

163

View full text Add to dashboard Cite

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“…Furthermore, Sting Ϫ/Ϫ mice more readily succumb to HSV-1 infection and fail to generate appropriate adaptive immune responses to DNA vaccines (21). Importantly, STING is widely expressed across many tissues and cell types (18,19) and phylogenetically conserved within vertebrates (22). Furthermore, the demonstration that its C terminus recruits the kinase TANK-binding kinase 1 (TBK-1) (23), in turn phosphorylating and activating the transcription factor IRF3 (24 -27), mechanistically linked STING to established type I IFN signaling factors and solidified its central role as an immune signaling hub (27).…”

Section: Cellular Dna-sensing Pathwaysmentioning

confidence: 99%

The Emerging Role of Nuclear Viral DNA Sensors

Diner

Lum

Cristea

2015

Journal of Biological Chemistry

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Detecting pathogenic DNA by intracellular receptors termed "sensors" is critical toward galvanizing host immune responses and eliminating microbial infections. Emerging evidence has challenged the dogma that sensing of viral DNA occurs exclusively in sub-cellular compartments normally devoid of cellular DNA. The interferon-inducible protein IFI16 was shown to bind nuclear viral DNA and initiate immune signaling, culminating in antiviral cytokine secretion. Here, we review the newly characterized nucleus-originating immune signaling pathways, their links to other crucial host defenses, and unique mechanisms by which viruses suppress their functions. We frame these findings in the context of human pathologies associated with nuclear replicating DNA viruses.Existing under the constant risk of invasion by pathogenic microorganisms, mammalian cells employ an array of constitutively expressed, germ-line-encoded receptors to survey the intra-and extracellular milieu for pathogen-or damage-associated molecules. Binding of these cellular receptors to their specific ligands evokes intracellular immune signaling cascades that culminate in the robust expression and secretion of antiviral cytokines, such as type I interferons (IFNs). Upon their release from the cell, these induced signaling factors operate in both an autocrine and a paracrine manner, inciting nearby cells to assume antiviral transcriptional programs. Cytokines further stimulate mammalian innate and adaptive immune responses, including the recruitment of antigen-presenting or cytotoxic leukocytes and the production of microbe-specific antibodies. Altogether, these cytokine-coordinated events promote the elimination of the invading pathogen. Thus, the molecular mechanisms mediating the recognition of and response to microbial molecular signatures are critically important.The DNA genomes of DNA viruses, a class of prevalent human pathogens, serve as one such immunogenic molecular signature. For preventing spurious auto-activation with cellular "self" DNA, the intracellular surveillance of viral DNA was thought to occur exclusively in cytosolic and endosomal compartments. However, this model fails to reconcile the fact that nearly all DNA viruses deposit and replicate their DNA genomes exclusively within host nuclei. As part of a shifting paradigm, recent studies have established the existence of cellular DNA sensors that detect viral DNA within the nucleus to trigger immune signaling. Here, we review the recent discoveries and ongoing challenges within the emerging field of nuclear DNA sensing.

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“…Another possibility is that zebrafish does not have the cGAS functional counterpart at all. cGAS is not present in all mouse cell types, and its antiviral function is replaced by other DNA sensors in specific cell types (45). We speculate that cGAS probably evolved later in the animal domain.…”

Section: Hsv-1 Induces Robust Antiviral Responses In Zebrafishmentioning

confidence: 86%

Conservation of the STING-Mediated Cytosolic DNA Sensing Pathway in Zebrafish

Zhou

Peng

et al. 2015

J Virol

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Zebrafish (Danio rerio) is a unique potential model animal for dissecting innate immune signaling. Here we demonstrate that herpes simplex virus 1 (HSV-1) could infect zebrafish at its different developmental stages and trigger the expression of type I interferons (IFNs) as well as interferon-stimulated genes (ISGs) in zebrafish larvae. Silencing of zSTING, but not zMAVS, markedly attenuates the DNA virus-induced antiviral responses. Notably, a conserved serine residue (S373) is essential for the action of zSTING. Unexpectedly, zebrafish cyclic GMP-AMP synthase (cGAS) is dispensable for the STING signaling, whereas zDHX9 and zDDX41 are potential sensors for HSV-1 infection in vivo. Taken together, this proof-of-concept study establishes the zebrafish larva as a feasible model for investigating the cytosolic DNA sensing mechanism, shedding light on the conservation of the STING antiviral signaling pathway. IMPORTANCEThe zebrafish larva provides technical advantages for understanding host-pathogen interactions. In this study, we established the zebrafish larva as a useful model for studying HSV-1 infection. HSV-1 infection triggers strong type I interferon production, which depends on STING expression. In addition, STING-mediated antiviral signaling is conserved in zebrafish. Interestingly, zDHX9 and zDDX41 are indispensable for detecting HSV-1, while cGAS is dispensable. This proof-of-concept study indicates that the zebrafish represents an amenable model for the investigation of cytosolic DNA sensing mechanisms.

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Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING

Cited by 164 publications

References 82 publications

An updated molecular basis for mussel immunity

An updated molecular basis for mussel immunity

The Emerging Role of Nuclear Viral DNA Sensors

Conservation of the STING-Mediated Cytosolic DNA Sensing Pathway in Zebrafish

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