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Inhibiting DDX3X triggers tumor-intrinsic type I interferon response and enhances anti-tumor immunity

ABSTRACT: Accumulating evidence has shown that cellular double-stranded RNAs (dsRNAs) induce antiviral innate immune responses in human normal and malignant cancer cells. However, it is not fully understood how endogenous ‘self’ dsRNA homeostasis is regulated in the cell. Here, we show that an RNA-binding protein, DEAD-box RNA helicase 3X (DDX3X), prevents the aberrant accumulation of cellular dsRNAs. Loss of DDX3X induces dsRNA sensor-mediated type I interferon signaling and innate immune response in breast cancer cells due to abnormal cytoplasmic accumulation of dsRNAs. Dual depletion of DDX3X and a dsRNA-editing protein, ADAR1 synergistically activates the cytosolic dsRNA pathway in breast cancer cell. Moreover, inhibiting DDX3X enhances the antitumor activity by increasing tumor intrinsic-type I interferon response, antigen presentation, and tumor-infiltration of cytotoxic T cells as well as dendritic cells in breast tumors, which may lead to the development of breast cancer therapy by targeting DDX3X in combination with immune checkpoint blockade. To assess the impact of DDX3X on the gene expression in the breast cancer, we stably depleted DDX3X in breast cancer MCF7 cells using a short hairpin RNA (shRNA)-mediated knockdown, and performed a genome-wide transcriptome analysis using a next-generation RNA deep sequencing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157323 | GEO | 2020/09/03

REPOSITORIES: GEO

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Expression profiling of DDX3X and DDX54 knockdown in MCF7 cells

Project description:We performed RNA-seq to observe the gene expression changes in cells following siRNA-mediated knockdown of DDX3X and DDX54 RNA helicases in human breast cancer MCF7 cells. Two siRNAs were used to target each RNA helicase and scramble siRNA-treated MCF7 cells were used as controls.

2018-11-21 | E-MTAB-6235 | biostudies-arrayexpress

iCLIP of DDX3X and DDX54 in human breast cancer MCF7 cells

Project description:Individual nucleotide resolution cross-linking immunoprecipitation (iCLIP) detects protein-RNA binding sites at a single nucleotide resolution. We aimed to identify the transcripts directly bound to DDX3X and DDX54 in human breast cancer MCF7 cells and to characterize the site of interaction at a single nucleotide resolution.

2018-11-21 | E-MTAB-6230 | biostudies-arrayexpress

ChIPseq of DDX3X, DDX54, ERalpha and H3K4me3 in human breast cancer MCF7 cells

Project description:We aimed to investigate the chromatin binding activity of DDX3X and DDX54 RNA helicases in human ER -dependent breast cancer MCF7 cells. We run a parallel chromatin binding profiling of ER ChIP-seq. H3K4me3 profiling was used as a quality control of the ChIP-seq procedure.

2019-11-14 | E-MTAB-6211 | biostudies-arrayexpress

Multi-omics analysis of hematopoietic progenitors in the fetal liver of Mettl3 deficient mice

Project description:N6-methyladenosine (m6A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Conditional deletion of the m6A writer METTL3 in murine fetal liver results in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activates an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs are long, highly m6A modified in their native state, characterized by low folding energies and predominantly protein-coding. We identified coinciding activation of innate immune pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development. Keywords: innate immune response, dsRNA, RNA modification, N6-methyladenosine, METTL3, hematopoietic development, RNA-seq, H3K4me3, CUT&RUN, J2-RIP, dropseq, single cell RNA-seq, scRNA-seq, LSK, fetal liver

2020-06-01 | GSE148882 | 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

DDX3X regulation of global translation is impaired by medulloblastoma-associated mutations [RiboSeq]

Project description:Whole-genome sequencing recently identified recurrent missense mutations in the RNA helicase DDX3X in pediatric medulloblastoma (MB) and other tumors. The normal function of DDX3X is poorly understood, and the consequences of its cancer-associated mutations have not been explored. Here we used genomic, biochemical, cell biological, and animal modeling approaches to investigate normal DDX3X function and the impact of cancer-associated DDX3X mutations. Cross-linking immunoprecipitation–high-throughput sequencing (CLIPseq) analyses revealed that DDX3X binds primarily to ~1000 mature mRNA targets at binding sites spanning the full mRNA length; their enrichment in the coding regions suggests that DDX3X plays a role in translational elongation. The association of wild-type DDX3X with polysomes is consistent with this observation. Cancer-associated mutations result in loss of DDX3X from polysomes and accumulation of mutant DDX3X in stress granules (cytoplasmic accumulations of translationally arrested mRNAs). Mutation-dependent redistribution of DDX3X to stress granules is also observed in a Drosophila model system and in MB tumor cells from patients carrying DDX3X mutations. Importantly, mRNAs targeted by DDX3X are enriched in translation factors, suggesting that DDX3X regulates translation both directly and indirectly. Indeed, depletion of DDX3X by RNAi or over-expression of mutant DDX3X significantly impairs global protein synthesis. Ribosome profiling confirmed this observation and showed a 5’ bias in ribosomal occupancy, further confirming the role of DDX3X in translational elongation. Together, our data show that DDX3X is a key regulator of translation and that this function is impaired by cancer-associated mutations. Finally, we found that medulloblastoma-related mutant DDX3X can efficiently bind the wild-type form suggesting that mutant DDX3X could exert a dominant negative effect in vivo.

2016-05-20 | GSE59095 | GEO

Medulloblastoma associated DDX3X mutants restore malignant potential of medulloblastoma cells decreased upon the loss of DDX3X expression

Project description:DDX3X is an ATP-dependent RNA helicase. Missense mutations in DDX3X gene are known to occur in WNT, SHH subgroup medulloblastomas. The role of DDX3X in medulloblastoma biology was studied by downregulating its expression in a SHH subgroup Daoy medulloblastoma cell line. DDX3X knockdown resulted in considerable reduction in proliferation, clonogenic potential and anchorage-independent growth of the medulloblastoma cells. Transcriptome analysis was performed to delineate the molecular mechanism underlying reduction in the malignant potential of the medulloblastoma cells upon DDX3X knockdown. Exogenous expression of three DDX3X missense mutants in the DDX3X knockdown cells could restore the malignant potential of the medulloblastoma cells.

2023-03-31 | GSE201967 | GEO

DDX3X regulation of global translation is impaired by medulloblastoma-associated mutations [CLIP-Seq]

2016-05-20 | GSE59094 | GEO

DDX3X regulation of global translation is impaired by medulloblastoma-associated mutations [RNA-Seq]

2016-05-20 | GSE59093 | GEO

RNA Helicase DDX3X Modulates Herpes Simplex Virus 1 Nuclear Egress

Project description:DDX3X is a mammalian RNA helicase that regulates RNA metabolism, cancers, innate immunity and several RNA viruses. We discovered that herpes simplex virus 1, a nuclear DNA replicating virus, highjacks redirects DDX3X to the nuclear envelope where it surprisingly modulates the exit of newly assembled viral particles. DDX3X depletion also led to an accumulation of virions in intranuclear herniations. Mechanistically, we show that DDX3X physically and functionally interacts with the virally encoded nuclear egress complex at the inner nuclear membrane. DDX3X also bound to and stimulated the incorporation in mature particles of pUs3, a herpes kinase that promotes viral nuclear release across the outer nuclear membrane. Overall, the data highlights two unexpected roles for an RNA helicase during the passage of herpes simplex viral particles through the nuclear envelope. This reveals a highly complex interaction between DDX3X and viruses and provides new opportunities to target viral propagation.

2023-02-21 | PXD039403 | Pride

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