Nucleic Acid Sensors and Programmed Cell Death

Maelfait, Jonathan; Liverpool, Layal; Rehwinkel, Jan

doi:10.1016/j.jmb.2019.11.016

Cited by 67 publications

(66 citation statements)

References 213 publications

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“…cGAS induces phosphorylation of IRF3 and stimulates apoptosis when mitosis is aberrantly arrested [3]. STING is implicated in the control of apoptosis and other modes of cell death in diverse scenarios of cell damage [5,6]. Therefore, the absence of cGAS and STING suggests that, besides antiviral defense, the induction of programmed cell death in response to endogenous DNA is reduced in pangolins.…”

Section: Discussionmentioning

confidence: 99%

“…These responses include the production of type I and type III interferons, interleukin (IL)-1 and 18 which transmit a danger signal to neighboring cells and activate the immune system. At the cellular level, mislocalized DNA can trigger senescence and programmed cell death [4][5][6]. Cell death is particularly important in host defense against DNA viruses, such as vaccinia virus, enterovirus A71, and herpes viruses, and bacteria, such as Mycobacterium tuberculosis variant bovis, Listeria monocytogenes, Legionella pneumophila, and Francisella tularenis, but also in sterile inflammation and cancer [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…By an as-yet unclear mechanism, also NF-κB is activated by STING, leading to the expression of inflammatory cytokines such as tumor necrosis factor (TNF). Via TNF and other pathways, activation of the cGAS-STING pathway triggers various types of programmed cell death including, necroptosis, apoptosis, and lysosomal cell death [5,6].…”

Section: Introductionmentioning

confidence: 99%

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Cytosolic DNA sensing through cGAS and STING is inactivated by gene mutations in pangolins

2020

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The release of DNA into the cytoplasm upon damage to the nucleus or during viral infection triggers an interferon-mediated defense response, inflammation and cell death. In human cells cytoplasmic DNA is sensed by cyclic GMP-AMP Synthase (cGAS) and Absent In Melanoma 2 (AIM2). Here, we report the identification of a "natural knockout" model of cGAS. Comparative genomics of phylogenetically diverse mammalian species showed that cGAS and its interaction partner Stimulator of Interferon Genes (STING) have been inactivated by mutations in the Malayan pangolin whereas other mammals retained intact copies of these genes. The coding sequences of CGAS and STING1 are also disrupted by premature stop codons and frame-shift mutations in Chinese and tree pangolins, suggesting that expression of these genes was lost in a common ancestor of all pangolins that lived more than 20 million years ago. AIM2 is retained in a functional form in pangolins whereas it is inactivated by mutations in carnivorans, the phylogenetic sister group of pangolins. The deficiency of cGAS and STING points to the existence of alternative mechanisms of controlling cytoplasmic DNA-associated cell damage and viral infections in pangolins.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cytosolic DNA sensing through cGAS and STING is inactivated by gene mutations in pangolins

2020

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“…In mammalian cells, nucleic acids of microbiome and host origin represent important signals for innate immunity. Cytosolic PRRs, including RIG‐I‐like receptors (RLRs) that detect RNA, AIM2‐like receptors (ALRs), and cyclic GMP‐AMP synthase (cGAS) which sense DNA, play critical roles in inducing signaling cascades to mediate host defenses 16 . Membrane‐bound PRRs, including TLRs and CLRs, are extensively reviewed elsewhere, 11,17,18 Cytosolic receptors, including NLRs, RLRs, ALRs, RLRs, cGAS, and STING, will be further discussed in the present review.…”

Section: Structure and Function Of Innate Pattern Recognition Receptorsmentioning

confidence: 99%

The microbiome and cytosolic innate immune receptors

Liwinski

Zheng

Elinav

2020

Immunological Reviews

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The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune‐mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host‐environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide‐binding domain, leucine‐rich repeat‐containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)–like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid‐inducible gene‐I (RIG‐I)–like receptors (RLRs), cyclic GMP‐AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host‐microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.

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“…Besides cGAS-STING pathway, multiple distinct DNA sensing pathways were identified in different types of cells over the last two decades, which can be activated in response to the presence of nucleic acids in the cytosol of cells [ 12 ]. Proteins that sense DNA i.e., DNA sensors can be endosomic or cytosolic [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

Jesenko

Bošnjak

Markelc

et al. 2020

Cancers

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Irradiation of tumors generates danger signals and inflammatory cytokines that promote the off-target bystander and abscopal effects, evident especially when radiotherapy is administered in combination with the immune checkpoint inhibitors (ICI). The underlying mechanisms are not fully understood; however, cGAS-STING pathway was recognized as the main mediator. In our study, we demonstrate by immunofluorescent staining that tumor cells as well as macrophages, cell types abundant in the tumor microenvironmeent (TME) accumulate DNA in their cytosol soon after irradiation. This accumulation activated several distinct DNA sensing pathways, most prominently activated DNA sensors being DDX60, DAI, and p204 in tumor cells and DDX60, DAI, p204, and RIG-I in macrophages as determined by PCR and immunofluorescence imaging studies. This was accompanied by increased expression of cytokines evaluated by flow cytometry, TNFα, and IFNβ in tumor cells and IL1β and IFNβ in macrophages, which can alter the TME and mediate off-target effects (bystander or abscopal effects). These results give insight into the mechanisms involved in the stimulation of antitumor immunity by radiation.

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Nucleic Acid Sensors and Programmed Cell Death

Cited by 67 publications

References 213 publications

Cytosolic DNA sensing through cGAS and STING is inactivated by gene mutations in pangolins

Cytosolic DNA sensing through cGAS and STING is inactivated by gene mutations in pangolins

The microbiome and cytosolic innate immune receptors

Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

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