RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I
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ABSTRACT:
PROVIDER: PRJNA763866 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15913894.fastq.gz | Fastqsanger.gz | |||
| SRR15913895.fastq.gz | Fastqsanger.gz | |||
| SRR15913896.fastq.gz | Fastqsanger.gz | |||
| SRR15913897.fastq.gz | Fastqsanger.gz | |||
| SRR15913898.fastq.gz | Fastqsanger.gz |
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Project description:RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/IKKε. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, TBK1, IKKε, IKKβ, and NF-κB p65. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol. To our knowledge, hnRNPM and ELAVL1 represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.
2023-09-16 | GSE184273 | GEO
Project description:RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/IKKε. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, TBK1, IKKε, IKKβ, and NF-κB p65. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol. To our knowledge, hnRNPM and ELAVL1 represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.
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Project description:The cytosolic nucleic acid sensors RIG-I and cGAS induce type-I interferon (IFN)-mediated immune responses to RNA and DNA viruses, respectively, but the underlying pathways remain incompletely understood. Here, we identify heterogeneous nuclear ribonucleoprotein M (hnRNPM) as a positive regulator of IRF3 phosphorylation and type-I IFN induction downstream of both cGAS and RIG-I. Combining interactome analysis with genome editing, we further uncover the RNA-binding protein ELAV-like protein 1 (ELAVL1; also known as human antigen R, HuR) as an hnRNPM interactor. Depletion of hnRNPM or ELAVL1 impairs type-I IFN induction by herpes simplex virus 1 or Sendai virus. In addition, we show that hnRNPM and ELAVL1 interact with TANK-binding kinase 1, IκB kinase ε, IκB kinase β, and NF-κB p65. Our confocal microscopy experiments demonstrate cytosolic and perinuclear interactions between hnRNPM, ELAVL1, and TBK1. Furthermore, pharmacological inhibition of ELAVL1 strongly reduces cytokine release from type-I interferonopathy patient fibroblasts. The RNA-binding proteins hnRNPM and ELAVL1 are the first non-redundant regulators to bridge the cGAS/STING and RIG-I/MAVS pathways. Overall, our study characterizes the hnRNPM-ELAVL1 complex as a novel system promoting antiviral defense, pointing to a potential therapeutic target to reduce auto-inflammation in patients with type-I interferonopathies.
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Project description:Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein hnRNPM promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFb signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFb-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44s splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial-splicing regulator that binds to the same cis-regulatory RNA elements and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program. RNAseq for control, hnRNPM siRNA treated lung metastatic LM2 clonal line, derived from the mesenchymal MDA-MB-231 cells
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Project description:Cancer cells are differentially dependent on the splicing machinery compared to normal untransformed cells. The splicing machinery thus presents a potential therapeutic target in cancer. To identify splicing factors important for prostate cancer cell (PCa) growth, we performed an unbiased pooled shRNA screen in in vitro passaged cells and in vivo xenografted PCa tumors. Our screen revealed HNRNPM as a potential regulator of PCa cell growth. RNA- and eCLIP- sequencing data suggest that HNRNPM is bound to key homeostatic genes, and that loss of HNRNPM binding in a subset of these genes results in aberrant exon inclusion and exon back-splicing events in target transcripts. In mis-spliced transcripts, HNRNPM appears to preferentially bind to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent splicing events using antisense oligonucleotides was sufficient to inhibit cell growth in HNRNPM expressing cells, suggesting that inhibition of cell growth in HNRNPM deficient cells likely has a multi-genic component. Taken together, our data reveal a role for HNRNPM in regulating PCa cell growth, and also as a potential therapeutic target in PCa.
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Project description:Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein hnRNPM promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFb signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFb-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44s splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial-splicing regulator that binds to the same cis-regulatory RNA elements and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.
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