cGAS-STING Signaling Pathway Mediates Brain Trauma-Induced Type I Interferon Response

Abstract Background Inflammation is a key contributor of neuronal death and dysfunction following traumatic brain injury (TBI). Recent evidence suggests that interferons may be a key regulator of this response. Our studies evaluated the role of the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) signaling pathway a murine model of TBI. Methods Male, eight-week old wildtype, STING knockout ( -/- ), cGAS -/- , and NLRX1 -/- mice were subjected to controlled cortical impact (CCI) or sham injury. Histopathological evaluation of tissue damage was assessed using non-biased stereology, which was complemented by analysis at the mRNA and protein level using qPCR and western blot analysis, respectively. Results We found that STING and Type I interferon-stimulated genes were upregulated after CCI injury in a bi-phasic manner and that loss of cGAS or STING conferred neuroprotection concomitant with a blunted inflammatory response at 24 hours post-injury. cGAS -/- animals showed reduced motor deficit 4 days after injury (dpi), and amelioration of tissue damage was seen in both groups of mice up to 14 dpi. Given that cGAS requires a cytosolic damage- or pathogen- associated molecular pattern (DAMP/PAMP) to prompt downstream STING signaling, we further show that mitochondrial DNA is present in the cytosol after TBI. Finally, our findings demonstrate that NLRX1 may be an additional regulator that functions upstream to regulate cGASSTING pathway. Conclusions These findings suggest that the canonical cGAS-STING-mediated Type I interferon signaling axis is a critical component of neural tissue damage following TBI and that mtDNA may be a possible trigger in this response.

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Positive natural selection in primate genes of the type I interferon response

BMC Ecology and Evolution ◽

10.1186/s12862-021-01783-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Elena N. Judd ◽

Alison R. Gilchrist ◽

Nicholas R. Meyerson ◽

Sara L. Sawyer

Keyword(s):

Natural Selection ◽

Positive Selection ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Sequence Alignments ◽

Multiple Sequence ◽

Multiple Sequence Alignments ◽

Interferon Stimulated Genes ◽

Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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Activation of RIG-I-mediated antiviral signaling triggers autophagy through the MAVS-TRAF6-Beclin-1 signaling axis

10.1101/340323 ◽

2018 ◽

Cited By ~ 1

Author(s):

Na-Rae Lee ◽

Junsu Ban ◽

Noh-Jin Lee ◽

Chae-Min Yi ◽

Jiyoon Choi ◽

...

Keyword(s):

Type I Interferon ◽

Sendai Virus ◽

Feedback Mechanism ◽

Innate Immune ◽

Beclin 1 ◽

Interferon Response ◽

Type I ◽

Interferon Signaling ◽

Negative Feedback Mechanism ◽

Signaling Axis

AbstractAutophagy has been implicated in innate immune responses against various intracellular pathogens. Recent studies have reported that autophagy can be triggered by pathogen recognizing sensors, including Toll-like receptors and cyclic guanosine monophosphate-adenosine monophosphate synthase, to participate in innate immunity. In the present study, we examined whether the RIG-I signaling pathway, which detects viral infections by recognizing viral RNA, triggers the autophagic process. The introduction of polyI:C into the cytoplasm, or Sendai virus infection, significantly induced autophagy in normal cells but not in RIG-I-deficient cells. PolyI:C transfection or Sendai virus infection induced autophagy in the cells lacking type-I interferon signaling. This demonstrated that the effect was not due to interferon signaling. RIG-I-mediated autophagy diminished by the deficiency of mitochondrial antiviral signaling protein (MAVS) or tumor necrosis factor receptor-associated factor (TRAF)6, showing that the RIG-I-MAVS-TRAF6 signaling axis was critical for RIG-I-mediated autophagy. We also found that Beclin-1 was translocated to the mitochondria, and it interacted with TRAF6 upon RIG-I activation. Furthermore, Beclin-1 underwent K63-polyubiquitination upon RIG-I activation, and the ubiquitination decreased in TRAF6-deficient cells. This suggests that the RIG-I-MAVS-TRAF6 axis induced K63-linked polyubiquitination of Beclin-1, which has been implicated in triggering autophagy. Collectively, the results of this study show that the recognition of viral infection by RIG-I is capable of inducing autophagy to control viral replication. As deficient autophagy increases the type-I interferon response, the induction of autophagy by the RIG-I pathway might also contribute to preventing an excessive interferon response as a negative-feedback mechanism.ImportanceMammalian cells utilize various innate immune sensors to detect pathogens. Among those sensors, RIG-I recognizes viral RNA to detect intracellular viral replication. Although cells experience diverse physiological changes upon viral infection, studies to understand the role of RIG-I signaling have focused on the induction of type-I interferon. Autophagy is a process that sequesters cytosolic regions and degrades the contents to maintain cellular homeostasis. Autophagy participates in the immune system, and has been known to be triggered by some innate immune sensors, such as TLR4 and cGAS. We demonstrated that autophagy can be triggered by the activation of RIG-I. In addition, we also proved that MAVS-TRAF6 downstream signaling is crucial for the process. Beclin-1, a key molecule in autophagy, is translocated to mitochondria, where it undergoes K63-ubiquitination in a TRAF6-dependent manner upon RIG-I activation. As autophagy negatively regulates RIG-I-mediated signaling, the RIG-I-mediated activation of autophagy may function as a negative-feedback mechanism.

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Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells

Cell Death Discovery ◽

10.1038/s41420-021-00487-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Xi Chen ◽

Elisa Saccon ◽

K. Sofia Appelberg ◽

Flora Mikaeloff ◽

Jimmy Esneider Rodriguez ◽

...

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Interferon Response ◽

Type I ◽

Response Type ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Huh7 Cells ◽

Related Proteins

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce the susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV, and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon-stimulated genes and their role in the inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.

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Cytosolic D‐type CpG‐oligonucleotides induce a type i interferon response by activating the cGAS‐STING signaling pathway

European Journal of Immunology ◽

10.1002/eji.202048810 ◽

2021 ◽

Author(s):

Christian Bode ◽

Jens M. Poth ◽

Mario Fox ◽

Susanne Schulz ◽

Dennis M. Klinman ◽

...

Keyword(s):

Signaling Pathway ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Cpg Oligonucleotides

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Human plasmacytoid dendritic cells elicit a Type I Interferon response by sensing DNA via the cGAS-STING signaling pathway

European Journal of Immunology ◽

10.1002/eji.201546113 ◽

2016 ◽

Vol 46 (7) ◽

pp. 1615-1621 ◽

Cited By ~ 33

Author(s):

Christian Bode ◽

Mario Fox ◽

Poonam Tewary ◽

Almut Steinhagen ◽

Richard K. Ellerkmann ◽

...

Keyword(s):

Dendritic Cells ◽

Signaling Pathway ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

Interferon Response ◽

Type I

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Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells

10.1101/2021.02.04.429738 ◽

2021 ◽

Author(s):

Xi Chen ◽

Elisa Saccon ◽

K. Sofia Appelberg ◽

Flora Mikaeloff ◽

Jimmy Esneider Rodriguez ◽

...

Keyword(s):

Immune Responses ◽

Type I Interferon ◽

Innate Immune ◽

Interferon Response ◽

Type I ◽

Response Type ◽

Innate Immune Responses ◽

Interferon Stimulated Genes ◽

Huh7 Cells ◽

Related Proteins

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-β production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon stimulated genes and their role in inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.

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