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Ablation of Adar1 in myeloid cells imprints a global antiviral state in the lung and heightens early immunity against SARS-CoV-2 [RNA-Seq]

ABSTRACT: Under normal homeostatic conditions, self double-stranded RNA (self-dsRNA) is modified by adenosine deaminase acting on RNA 1 (ADAR1) to prevent the induction of a type I interferon (IFN) mediated inflammatory cascade. Antigen presenting cells (APCs) sense pathogen associated molecular patterns (PAMPs), such as dsRNA, to activate the immune response. The impact of ADAR1 on the function of APCs and the consequences on immunity is poorly understood. Here, we show that ADAR1 deletion in CD11c+ APCs leads to: (i) a skewed myeloid cell compartment enriched in inflammatory cDC2s (inf-cDC2) like cells; (ii) enhanced numbers of activated tissue resident memory T cells (TRMs) in the lung; and (iii) the imprinting of a broad antiviral transcriptional signature across both immune and non-immune cells. Further the resulting changes can be partially reversed by blocking IFNAR1 signaling and promote early resistance against SARS-CoV-2 infection. Our study provides insight into the consequences of self-dsRNA sensing in APCs on the immune system in the context of viral challenge.

ORGANISM(S): Mus musculus

PROVIDER: GSE222326 | GEO | 2023/01/22

REPOSITORIES: GEO

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Ablation of Adar1 in myeloid cells imprints a global antiviral state in the lung and heightens early immunity against SARS-CoV-2 [scRNA-Seq]

Project description:Under normal homeostatic conditions, self double-stranded RNA (self-dsRNA) is modified by adenosine deaminase acting on RNA 1 (ADAR1) to prevent the induction of a type I interferon (IFN) mediated inflammatory cascade. Antigen presenting cells (APCs) sense pathogen associated molecular patterns (PAMPs), such as dsRNA, to activate the immune response. The impact of ADAR1 on the function of APCs and the consequences on immunity is poorly understood. Here, we show that ADAR1 deletion in CD11c+ APCs leads to: (i) a skewed myeloid cell compartment enriched in inflammatory cDC2s (inf-cDC2) like cells; (ii) enhanced numbers of activated tissue resident memory T cells (TRMs) in the lung; and (iii) the imprinting of a broad antiviral transcriptional signature across both immune and non-immune cells. Further the resulting changes can be partially reversed by blocking IFNAR1 signaling and promote early resistance against SARS-CoV-2 infection. Our study provides insight into the consequences of self-dsRNA sensing in APCs on the immune system in the context of viral challenge.

2023-01-22 | GSE222487 | GEO

ADAR1 utilizes independent mechanisms to suppress MDA5 and PKR activation by cellular double-stranded RNA

Project description:The antiviral defense in vertebrates requires the innate immune system to sense foreign “non-self” nucleic acids while avoiding “self” nucleic acids, which is accomplished by an intricate system. Cellular double-stranded RNAs (dsRNAs) are edited by the RNA editing enzyme ADAR1 to prevent their dsRNA structure pattern from being recognized as viral dsRNA. Lack of RNA editing by ADAR1 enables activation of MDA5, a cytosolic dsRNA sensor, by cellular dsRNA. Additional RNA editing- independent functions of ADAR1 have been proposed, but the specific mechanism remains elusive. Here we demonstrate that RNA binding by ADAR1, independent of its editing activity, restricts the activation of PKR, another cytosolic dsRNA sensor, by cellular dsRNA. Mechanistically, the loss of ADAR1 editing caused MDA5 activation to induce interferon signaling, while a lack of ADAR1 protein or its dsRNA binding ability led to PKR activation, with subsequent stress granule formation and proliferation arrest. Based on these findings we rescued the Adar1−/− mice from embryonic lethality to adulthood by deleting both MDA5 and PKR, in contrast to the limited rescue of Adar1−/− mice by removing MDA5 or PKR alone. Our findings reveal a multifaceted contribution of ADAR1 in regulating the immunogenicity of “self” dsRNAs. Furthermore, ADAR1 is an immuno-oncology target for drug development, and the separation of ADAR1’s RNA editing and binding functions provides mechanistic insights for such developments.

2023-10-03 | GSE198386 | GEO

Malignant A-to-I RNA editing by ADAR1 drives T-cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing

Project description:Leukemia initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches to eliminate LICs and prevent relapse. Here, we show that the RNA editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine (A-to-I) editing is a common attribute of relapsed T-ALL regardless of molecular subtypes. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL PDX models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor MDA5. Moreover, we uncovered that the cell intrinsic level of MDA5 dictates the dependency on ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs.

2023-12-31 | GSE221112 | GEO

The RNA editing enzyme ADAR1 is a key regulatory of innate immune responses to RNA

Project description:The ADAR RNA editing enzymes deaminate adenosine bases to inosines in cellular RNAs, recoding open reading frames. Human ADAR1 mutations cause Aicardi-Goutieres Syndrome (AGS) and Adar1 mutant mice showing an aberrant interferon response and death by embryonic day E12.5 model the human disease. Searches have not identified key ADAR1 RNA editing sites recoding immune/haematopoietic proteins but editing is widespread in Alu sequences. We show that Adar1 embryonic lethality is rescued in Adar1; Mavs double mutant mice in which general antiviral responses to cytoplasmic dsRNA are prevented. We propose that inosine bases are epigenetic marks identifying cellular RNA as innate immune ÒselfÓ. Consistent with this idea we show that an editing-active cytoplasmic ADAR is required to prevent aberrant immune responses in Adar1 mutant mouse embryo fibroblasts. No dramatic increase in repetitive transcripts is observed. AGS mutations in ADAR1 affect editing by the interferon-inducible cytoplasmic ADAR1 isoform. RNA-seq expression profiling in Adar1 and Adar1/Mavs knockout mice embryos.

2014-12-19 | E-GEOD-62917 | biostudies-arrayexpress

RNA editing is the essential function of ADAR1 and, in the absence of MDA5, is dispensable for normal adult homeostasis [RNAseq (Fetal Brain)]

Project description:Adenosine-to-Inosine (A-to-I) editing of dsRNA by ADAR proteins is a pervasive feature of the epitranscriptome. There are estimated to be over 100 million potential A-to-I editing sites in humans and A-to-I editing can have varying consequences for gene expression. Whilst editing resulting in protein recoding defines the role of ADAR2, ADAR1 has been proposed to have both editing-dependent and -independent functions. The relative contribution of these putative functions to ADAR1 biology is unclear. We demonstrate that the absence of ADAR1-mediated editing is well tolerated when the cytosolic dsRNA sensor MDA5 is deleted. These mice have normal hematopoiesis, tissue patterning and life span. A direct comparison of the complete deletion of ADAR1 and the specific loss of A-to-I editing activity demonstrates that RNA editing is the only essential function of ADAR1 in adult mice. Therefore, preventing MDA5 substrate formation by endogenous RNA is the essential in vivo function of ADAR1-mediated editing.

2017-08-14 | GSE94388 | GEO

RNA editing is the essential function of ADAR1 and, in the absence of MDA5, is dispensable for normal adult homeostasis [mmPCR-seq]

2017-08-14 | GSE94386 | GEO

RNA editing is the essential function of ADAR1 and, in the absence of MDA5, is dispensable for normal adult homeostasis [RNAseq (Adult Brain)]

2017-08-14 | GSE94387 | GEO

ADAR1 suppression in human astrocytes

Project description:ADAR1 regulates the accumulation of endeognouse double-stranded RNA (dsRNA), a pro-inflammatory/innate immune activator. The purpose of this study was to measure the effects of ADAR1 suppression in human astrocytes and determine RNAs regulated by ADAR1. Primary human astrocytes were culture and transfected with a scramble or ADAR1 siRNA. RNA was isolated from these cells for total RNA-seq to analyze changes in gene/repetitive element expression and RNA editing.

2023-09-07 | GSE225369 | GEO

Long 3'UTRs predispose neurons to inflammation by promoting immunostimulatory double-stranded RNA formation

Project description:Loss of RNA homeostasis underlies numerous neurodegenerative and neuroinflammatory diseases. However, the molecular mechanisms that trigger neuroinflammation are poorly understood. Viral double-stranded RNA (dsRNA) triggers innate immune responses when sensed by host pattern recognition receptors (PRRs) present in all cell types. Here, we report that human neurons intrinsically carry exceptionally high levels of immunostimulatory dsRNAs and identify long 3'UTRs as giving rise to neuronal dsRNA structures. We found that the neuron-enriched ELAVL family of genes (ELAVL2, -3, -4) can increase 1) 3'UTR length, 2) dsRNA load, and 3) activation of dsRNA-sensing PRRs such as MDA5, PKR, and TLR3. In wild-type neurons, neuronal dsRNAs signaled through PRRs to induce tonic production of the antiviral type I interferon. Depleting ELAVL2 in WT neurons led to global shortening of 3'UTR length, reduced immunostimulatory dsRNA levels, and rendered WT neurons susceptible to herpes simplex virus and Zika virus infection. Neurons deficient in ADAR1, a dsRNA-editing enzyme mutated in the neuroinflammatory disorder Aicardi-Goutières syndrome, exhibited intolerably high levels of dsRNA that triggered PRR mediated toxic inflammation and neuronal death. Depleting ELAVL2 in ADAR1 knockout neurons led to prolonged neuron survival by reducing immunostimulatory dsRNA levels. In summary, neurons are specialized cells where PRRs constantly sense ‘self’ dsRNAs to pre-emptively induce protective antiviral immunity, but maintaining RNA homeostasis is paramount to prevent pathological neuroinflammation.

2023-10-20 | GSE214949 | GEO

The RNA editing enzyme ADAR1 is a key regulatory of innate immune responses to RNA

2014-12-19 | GSE62917 | GEO

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