GGNBP2 regulates MDA5 sensing triggered by self double stranded RNA following loss of ADAR1 editing
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA982066 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24738500_1.fastq.gz | Fastqsanger.gz | |||
| SRR24738500_2.fastq.gz | Fastqsanger.gz | |||
| SRR24738501_1.fastq.gz | Fastqsanger.gz | |||
| SRR24738501_2.fastq.gz | Fastqsanger.gz | |||
| SRR24738502_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 186 |
Similar Datasets
Project description:Adenosine-to-Inosine (A-to-I) editing of double stranded RNA (dsRNA) is an essential modifier of dsRNA immunogenicity. Loss of Adenosine deaminase acting on RNA 1 (ADAR1), or its A-to-I editing activity, triggers a lethal MDA5-dependent autoinflammatory response to endogenous unedited dsRNA. We performed a genome-wide suppressor screen to map the genetic landscape regulating the response to a loss of ADAR1 mediated A-to-I editing. This identified that the interacting proteins GGNBP2, CNOT10 and CNOT11 regulate immunogenic sensing following loss of A-to-I editing. GGNBP2 acts between transcription and cytoplasmic MDA5 sensing. Loss of GGNBP2 modified the distribution of dsRNA within cells, reducing the cytoplasmic dsRNA load and preventing induction of type I IFN and lethal autoinflammation. GGNBP2, CNOT10 and CNOT11 are novel regulators of the cellular response to unedited dsRNA.
2024-11-21 | GSE234570 | GEO
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
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
Project description:Adenosine deaminases acting on RNA (Adar1 and Adar2) catalyze I-to-A RNA editing, a post-transcriptional mechanism involved in multiple cellular functions. The role of Adar1-dependent RNA editing in cardiomyocytes (CMs) remains unclear. Here we show that conditional deletion of Adar1 in CMs results in myocarditis progressively evolving into dilated cardiomyopathy and heart failure at only 6 months of age. Adar1 depletion drives activation of interferon signaling genes (ISGs) in the absence of apoptosis and cytokine activation, and reduces the hypertrophic response of CMs upon pressure overload. Interestingly, ablation of the cytosolic sensor MDA5 prevents cardiac ISG activation and delays disease onset, but does not rescue the long-term lethal phenotype elicited by conditional deletion of Adar1. Retention of a single catalytically inactive Adar1 allele in CMs, in combination with MDA5 depletion, however, completely restores the cardiac function and prevents heart failure. Finally, ablation of interferon regulatory factor 7 (Irf7) attenuates the phenotype of Adar1-deficient CMs to a similar extent as MDA5 depletion, highlighting Irf7 as the main regulator of the immune response triggered by lack of Adar1 in CMs.
2022-08-24 | PXD024974 | Pride
Project description:ADAR1 utilizes independent mechanisms to suppress MDA5 and PKR activation by cellular double-stranded RNA
| PRJNA814746 | ENA
Project description:Sensing of double-stranded RNA (dsRNA) is an important component of innate immunity. Proteins like PKR and MDA5 recognize dsRNA and activate various pathways to fight viral infection. In addition to viral dsRNA, many endogenous RNAs containing double-stranded regions can be misrecognized as immunogenic. The RNA editing enzyme ADAR1, specifically its p150 isoform, has been shown to suppress activation of PKR and MDA5 through its A-to-I editing activity. While the cytoplasmic ADAR1-p150 isoform has been well established within this role, the functions of the nuclear ADAR1-p110 isoform are less understood. To address this knowledge gap, we utilized proximity labeling by APEX2 to identify putative ADAR1-p110 interacting proteins. We identified 110 proteins across three breast cancer cell lines that either interact with p110 or are within close proximity. Many of these proteins have known roles in RNA metabolism. Nine of the identified proteins belong to the DEAD or DEAH box families of RNA helicases, including DHX9. DHX9 is overexpressed in breast cancer, with expression closely correlated with that of p110. By co-immunoprecipitation we confirmed that p110 interacts with DHX9. Knockdown of DHX9 in several triple-negative breast cancer cell lines caused cell death and activation of the dsRNA sensor PKR. In two cell lines that are refractory to knockdown of ADAR1, the combined knockdown of DHX9 and ADAR1 caused a substantial increase in PKR activity, where knockdown of either alone had no effect. Knockdown of DHX9 and ADAR1 caused activation of the type I IFN pathway, RNase L and NF-KB signaling. Activation of these proteins and pathways was not seen with individual knockdown of ADAR1 or DHX9. Activation of PKR following combined knockdown of ADAR1 and DHX9 could be rescued by expression of p110, p150, DHX9, and catalytically inactive DHX9. Additionally PKR activation could be rescued by the dsRBM of DHX9, revealing an important role for dsRBMs in suppressing PKR activation. Together these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.
2023-08-07 | GSE224677 | GEO
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 | GSE94386 | GEO
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 | GSE94387 | GEO
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
Project description:ADAR1 is thought to be an immune suppressor maintaining self-tolerance to endogenous nucleic acids. Lack of ADAR1 results in MDA5 (Ifih1) activation and MDA5 deletion rescues ADAR1 null embryonic lethality. We generated liver specific ADAR1; MDA5 double KO mice and performed high throughput sequencing to investigate hepatic inflammation in these mice. Bulk RNA was sequenced on the HiSeq X platform. Over 100 million pairs of mappable reads for each sample were obtained.
2024-05-28 | GSE225175 | GEO