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Endocytosed dsRNAs induce lysosomal membrane permeabilization that allows cytosolic dsRNA translocation for Drosophila RNAi response

ABSTRACT: Endocytosed dsRNAs induce lysosomal membrane permeabilization that allows cytosolic dsRNA translocation for Drosophila RNAi response

PROVIDER: PRJNA1023479 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26264173.fastq.gz	Fastqsanger.gz
	SRR26264174.fastq.gz	Fastqsanger.gz
	SRR26264175.fastq.gz	Fastqsanger.gz
	SRR26264176.fastq.gz	Fastqsanger.gz
	SRR26264177.fastq.gz	Fastqsanger.gz

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Endocytosed dsRNAs induce lysosomal membrane permeabilization that allows cytosolic dsRNA translocation for Drosophila RNAi response

Project description:RNA interference (RNAi) is a gene-silencing mechanism triggered by the cytosolic entry of double-stranded RNAs (dsRNAs). Many animal cells internalize extracellular dsRNAs via endocytosis for RNAi induction. However, it is not clear how the endocytosed dsRNAs are translocated into the cytosol across the endo/lysosomal membrane. Herein, we show that in Drosophila S2 cells, endocytosed dsRNAs induce lysosomal membrane permeabilization (LMP) that allows cytosolic dsRNA translocation. LMP mediated by dsRNAs requires the lysosomal Cl−/H+ antiporter ClC-b/DmOstm1. In clc-b or dmostm1 knockout S2 cells, extracellular dsRNAs are endocytosed and reach the lysosomes normally but fail to enter the cytosol. Pharmacological induction of LMP restores extracellular dsRNA-directed RNAi in clc-b or dmostm1-knockout cells. Furthermore, clc-b or dmostm1 mutant flies are defective in extracellular dsRNA-directed RNAi and its associated antiviral immunity. Therefore, endocytosed dsRNAs have an intrinsic ability to induce ClC-b/DmOstm1-dependent LMP that allows cytosolic dsRNA translocation for RNAi responses in Drosophila cells.

2024-07-07 | GSE244523 | GEO

Cytosolic dsRNA-induced gene expression in mouse RAW24.7 macrophages and FIP200 knockout RAW cells

Project description:Our preliminary data showed that FIP200 is essential for dsRNA-induced interferon production. To corroborate the role of FIP200 in RIG-I signaling pathway, we are going to examine the cytosolic dsRNA-induced gene expression in mouse RAW24.7 macrophages and FIP200 knockout RAW cells.

2020-03-16 | GSE147001 | GEO

RNA 5-methylcytosine marks mitochondrial double-stranded RNAs for degradation and cytosolic release

Project description:Mitochondria are essential regulators of innate immunity. They generate long double-stranded RNAs (mt-dsRNAs) and release them to the cytosol to trigger immune response under pathological stress conditions. Yet, the regulation of these self-immunogenic RNAs remains largely unknown. Here, we employ CRISPR screening on RNA-binding proteins residing in mitochondria and identify NOP2/Sun RNA methyltransferase 4 (NSUN4) as a key regulator of mt-dsRNA expression. We find that NSUN4 induces 5-methylcytosine (m5C) modification on mitochondrial RNAs, especially on the termini of light-strand long noncoding RNAs. These m5C-modified RNAs are recognized by complement C1q binding protein (C1QBP), which recruits polyribonucleotide nucleotidyltransferase to facilitate RNA turnover. Suppression of NSUN4 or C1QBP results in increased mt-dsRNA expression while C1QBP deficiency also leads to increased cytosolic mt-dsRNAs and subsequent immune activation. Collectively, our study unveils the mechanism underlying the selective degradation of light-strand mitochondrial RNAs and establishes a molecular mark for mitochondrial RNA decay and cytosolic release.

2024-08-16 | GSE246026 | GEO

Effect of p53 on the expression of combo induced dsRNAs in 2153L GEM tumors

Project description:We analyzed the expression of dsRNAs in control and p53 restored 2153L GEM tumors upon different treatments. Our ChIP-seq and RNA-seq experiments showed that the restored p53 bound to the regulatory regions of dsRNA-containing genes that account for 91% of the total dsRNA abundance in combination therapy–treated 2153L tumors, and suppressed their expression upon combination therapy. The abundance of dsRNA (TPM) was calculated from the dsRIP experiment.

2024-10-16 | GSE276354 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of yeast cells lacking either M-2 dsRNA or both L-A-lus and M-2 dsRNA viruses

Project description:Here we determine the impact upon the loss of M-2 dsRNA alone and both L-A-lus along with M-2 on the host S. cerevisiae transcriptional changes. By performing profiling of the whole transcriptomes, we determined 486 genes differentially expressed after curing of yeast cells from M-2 dsRNA and 715 genes affected by the elimination of both M-2 and L-A-lus dsRNAs.

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Evidence of off-target effects associated with long dsRNAs in Drosophila cell-based assays

Project description:To evaluate the specificity of long dsRNAs used in high-throughput RNAi screens performed at the Drosophila RNAi Screening Center (DRSC), we performed a global analysis of their activity in 30 genome-wide screens completed at our facility. Surprisingly, our analysis predicts that dsRNAs containing ≥19 nucleotide perfect matches identified in silico to unintended targets may contribute to a significant false positive error rate arising from off-target effects. We confirmed experimentally that such sequences in dsRNAs lead to false positives and to the efficient knockdown of a cross-hybridizing transcript, raising a cautionary note when interpreting results based on the use of a single dsRNA per gene. Although a full appreciation of all causes of false positive errors remains to be determined, we suggest simple guidelines to help ensure high quality information from RNAi high-throughput screens Keywords: Specificity of long dsRNAs, Drosophila melanogaster, SL2 cell line, custom cDNA arrays, off-target effects, Drosophila RNAi Screening Center (DRSC)

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Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.

2016-08-04 | E-GEOD-79508 | biostudies-arrayexpress

Cytosolic dsRNA-induced gene expression in mouse RAW24.7 macrophages and FIP200 knockout RAW cells

Project description:Cytosolic dsRNA-induced gene expression in mouse RAW24.7 macrophages and FIP200 knockout RAW cells

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Determination of dsRNA interactome upon Sindbis virus infection in human cells identifies SFPQ as a critical proviral factor

Project description:Viruses are obligate intracellular parasites, which depend on the host cellular machineries to replicate their genome and complete their infectious cycle. Long double stranded (ds)RNA is a common viral by-product originating during RNA virus replication, which is universally sensed as a danger signal to trigger the antiviral response. As a result, viruses hide dsRNA intermediates into viral replication factories and have evolved strategies to hijack cellular proteins for their benefit. The characterization of the host factors associated to viral dsRNA and involved in viral replication remains a major challenge to develop new antiviral drugs against RNA viruses. Here, we performed anti-dsRNA immunoprecipitation followed by Mass Spectrometry to fully characterize the dsRNA interactome in Sindbis virus (SINV) infected human HCT116 cells. Among the validated factors, we characterized SFPQ (Splicing factor, proline-glutamine rich) as a new dsRNA-associated factor upon SINV infection. We proved that SFPQ is able to directly bind dsRNAs in vitro, that SFPQ association to dsRNA is independent on single-stranded (ss)RNA flanking regions in vivo and that it is able to bind the viral genome upon infection. Furthermore, we showed that either knock-down or knock-out of SFPQ reduced SINV infection in human HCT116 and SKNBE cells, suggesting that SFPQ could enhance viral replication. Overall, this study not only represents a resource to further study SINV dsRNA-associated factors upon infection but also identifies SFPQ as a new proviral dsRNA binding protein.

2024-05-22 | PXD024554 | Pride

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

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