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Adar1 as a placental innate immune rheostat to prevent endogenous dsRNA-induced integrated stress response-dependent embryonic lethality [Adar1 PKO RNA-seq]

ABSTRACT: The mechanisms that balance a robust antiviral defense with tissue tolerance at the maternal-fetal interface under physiological conditions remain largely unknown.

ORGANISM(S): Mus musculus

PROVIDER: GSE279582 | GEO | 2025/10/29

REPOSITORIES: GEO

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Adar1 as a placental innate immune rheostat to prevent endogenous dsRNA-induced integrated stress response-dependent embryonic lethality

Project description:The mechanisms that balance a robust antiviral defense with tissue tolerance at the maternal-fetal interface under physiological conditions remain largely unknown.

2025-10-29 | GSE279053 | GEO

Adar1 as a placental innate immune rheostat to prevent endogenous dsRNA-induced integrated stress response-dependent embryonic lethality [RIP-seq]

Project description:The mechanisms that balance a robust antiviral defense with tissue tolerance at the maternal-fetal interface under physiological conditions remain largely unknown.

2025-10-29 | GSE279352 | GEO

Adar1 as a placental innate immune rheostat to prevent endogenous dsRNA-induced integrated stress response-dependent embryonic lethality [bulk RNA-seq]

Project description:The mechanisms that balance a robust antiviral defense with tissue tolerance at the maternal-fetal interface under physiological conditions remain largely unknown.

2025-10-29 | GSE279579 | GEO

Adar1 as a placental innate immune rheostat to prevent endogenous dsRNA-induced integrated stress response-dependent embryonic lethality [RIP-seq]

Project description:Adar1 as a placental innate immune rheostat to prevent endogenous dsRNA-induced integrated stress response-dependent embryonic lethality [RIP-seq]

| PRJNA1172134 | ENA

RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.

Project description:Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) enzymes. In addition to RNA editing, additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1, we generated mice with an editing-deficient knock-in mutation (Adar1(E861A), where E861A denotes Glu(861)→Ala(861)). Adar1(E861A/E861A) embryos died at ~E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)-sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3' untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of Adar1(E861A/E861A) were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts.

| S-EPMC5444807 | biostudies-literature

Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.

Project description:Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the RIG-I-like receptors (RLRs), which recognize viral dsRNA and initiate antiviral innate immune responses with the potential of triggering systemic inflammation and immunopathology. Here, we show that stress granules (SGs), molecular condensates that form in response to various stresses including viral dsRNA, play key roles in the controlled activation of RLR signaling. Without the SG nucleators G3BP1/2 and UBAP2L, dsRNA triggers excessive inflammation and immune-mediated apoptosis. In addition to exogenous dsRNA, host-derived dsRNA generated in response to ADAR1 deficiency is also controlled by SG biology. Intriguingly, SGs can function beyond immune control by suppressing viral replication independently of the RLR pathway. These observations thus highlight the multi-functional nature of SGs as cellular "shock absorbers" that converge on protecting cell homeostasis by dampening both toxic immune response and viral replication.

| S-EPMC10170497 | biostudies-literature

Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA

Project description:Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the innate immune receptors that recognize viral double-stranded RNA (dsRNA) and initiate antiviral immune responses with the potential of triggering systemic inflammation and immunopathology. How the functions of the dsRNA receptors and their downstream effector molecules are coordinately regulated to avoid excessive immune response is poorly understood. We here demonstrate that stress granules (SGs), biomolecular condensates that form in response to various stresses including viral dsRNA, play key roles in regulating dsRNA-triggered immune response. Upon dsRNA stimulation, SGs recruit many innate immune molecules, including RIG-I-like receptors (RLRs), protein kinase R (PKR) and oligoadenylate synthases (OASes), target these molecules and dsRNA for autophagy and limit their functions through sequestration. In the absence of SGs, dsRNA stimulation results in hyperactivation of inflammatory signaling pathways, global translational arrest and bulk RNA degradation, altogether compromising the cellular capacity to restore homeostasis and triggering cell death. In contrast to most dsRNA-induced immune signaling pathways that are hyperactivated in the absence of SGs, a sub-branch of the RLR pathway (IRF3-dependent type I interferon signaling) shows time-dependent changes, where the initial spike in signaling is followed by a significant drop due to increased caspase-dependent negative feedback regulation. This highlights the role of SGs in regulating the delicate balance between the type I interferon pathway and cell death. Altogether, our data suggest that cells utilize SGs as shock absorbers to moderate antiviral innate immune response, thereby allowing cells to guard against its own immune system as well as viruses.

2021-05-06 | GSE173953 | GEO

Cardiomyocyte Specific Deletion of ADAR1 Causes Severe Cardiac Dysfunction and Increased Lethality.

Project description:Background: Adenosine deaminase acting on RNA 1 (ADAR1) is a double-stranded RNA-editing enzyme that is involved in several functions including the deamination of adenosine to inosine, RNA interference (RNAi) mechanisms and microRNA (miRNA) processing, rendering ADAR1 essential for life. Methods and Results: To investigate whether maintenance of ADAR1 expression is required for normal myocardial homeostasis, we bypassed the early embryonic lethality of ADAR1-null mice through the use of a tamoxifen-inducible Cre recombinase under the control of the cardiac-specific α-myosin heavy chain promoter (αMHC). Targeted ADAR1 deletion in adult mice caused a significant increase in lethality accompanied by severe ventricular remodeling and quick and spontaneous cardiac dysfunction, induction of stress markers and overall reduced expression of miRNAs. Administration of a selective inhibitor of the unfolded protein response (UPR) stress significantly blunted the deleterious effects and improved cardiac function thereby prolonging animal survival. In vitro restoring miR-199a-5p levels in cardiomyocytes lacking ADAR1 diminished UPR activation and concomitant apoptosis. Conclusions: Our findings demonstrate an essential role for ADAR1 in cardiomyocyte survival and maintenance of cardiac function through a mechanism that integrates ADAR1 dependent miRNA processing and the suppression of UPR stress.

| S-EPMC7093378 | biostudies-literature

Human ADAR1 Prevents Endogenous RNA from Triggering Translational Shutdown.

Project description:Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.

| S-EPMC5831367 | biostudies-literature

SOX2 Reprograms the Esophageal Squamous Carcinoma Epigenome and Induces Endogenous Retroviral Elements and dsRNA, Thereby Promoting ADAR1 Dependence

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-03-17 | GSE167367 | GEO