MKRN2 physically interacts with GLE1 to regulate mRNA export and zebrafish retinal development
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ABSTRACT:
PROVIDER: PRJNA562493 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10045364.fastq.gz | Fastqsanger.gz | |||
| SRR10045365.fastq.gz | Fastqsanger.gz | |||
| SRR10045366.fastq.gz | Fastqsanger.gz |
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Project description:The canonical mammalian mRNA export process is thought to terminate at the cytoplasmic face of the nuclear pore complex through mRNP remodeling. We conducted a stringent affinity-purification mass-spectrometry-based screen of the physical interactions of human RNA-binding E3 ubiquitin ligases. The resulting protein-interaction network revealed unexpected interactions between the RNA-binding E3 ubiquitin ligase MKRN2 and GLE1, a DEAD-box helicase activator implicated in mRNA export termination. We assessed MKRN2 epistasis with GLE1 in a genetically tractable zebrafish model. Strikingly, morpholino-mediated knockdown or CRISPR/Cas9-based knockout of MKRN2 partially rescued retinal developmental defects seen upon GLE1 depletion. Next, using iCLIP, we showed that MKRN2 binds preferentially to the 3'UTR of a diverse subset of mRNAs. Next-generation sequencing of fractionated cell extracts revealed that nuclear export of MKRN2-associated mRNAs is enhanced upon knockdown of MKRN2. Taken together, these results indicate that MKRN2 selectively interacts with GLE1 to regulate mRNA nuclear export and retinal development.
2020-05-19 | GSE136399 | GEO
Project description:The canonical mammalian mRNA export process is thought to terminate at the cytoplasmic face of the nuclear pore complex through mRNP remodeling. We conducted a stringent affinity-purification mass-spectrometry-based screen of the physical interactions of human RNA-binding E3 ubiquitin ligases. The resulting protein-interaction network revealed unexpected interactions between the RNA-binding E3 ubiquitin ligase MKRN2 and GLE1, a DEAD-box helicase activator implicated in mRNA export termination. We assessed MKRN2 epistasis with GLE1 in a genetically tractable zebrafish model. Strikingly, morpholino-mediated knockdown or CRISPR/Cas9-based knockout of MKRN2 partially rescued retinal developmental defects seen upon GLE1 depletion. Next, using iCLIP, we showed that MKRN2 binds preferentially to the 3'UTR of a diverse subset of mRNAs. Next-generation sequencing of fractionated cell extracts revealed that nuclear export of MKRN2-associated mRNAs is enhanced upon knockdown of MKRN2. Taken together, these results indicate that MKRN2 selectively interacts with GLE1 to regulate mRNA nuclear export and retinal development.
2020-05-19 | GSE136421 | GEO
Project description:MKRN2 physically interacts with GLE1 to regulate mRNA export and zebrafish retinal development (RNA-Seq)
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Project description:The canonical mammalian mRNA nuclear export process is thought to terminate at the cytoplasmic face of the nuclear pore complex through ribonucleoprotein remodeling. We conducted a stringent affinity-purification mass-spectrometry-based screen of the physical interactions of human RNA-binding E3 ubiquitin ligases. The resulting protein-interaction network revealed interactions between the RNA-binding E3 ubiquitin ligase MKRN2 and GLE1, a DEAD-box helicase activator implicated in mRNA export termination. We assessed MKRN2 epistasis with GLE1 in a genetically tractable zebrafish model. Morpholino-mediated knockdown or CRISPR/Cas9-based knockout of MKRN2 partially rescued retinal developmental defects seen upon GLE1 depletion, consistent with a functional association between GLE1 and MKRN2. Using ribonomic approaches, we showed that MKRN2 binds selectively to the 3'UTR of a diverse subset of mRNAs and that nuclear export of MKRN2-associated mRNAs is enhanced upon knockdown of MKRN2. Taken together, we suggest that MKRN2 interacts with GLE1 to selectively regulate mRNA nuclear export and retinal development.
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Project description:Utilisation of RNA-binding proteins (RBPs) is an important aspect of post-transcriptional regulation of viral RNA. Viruses such as influenza A viruses (IAV) interact with RBPs to regulate processes including splicing, nuclear export and trafficking, while also encoding RBPs within their genomes, such as NP and NS1. But with almost 1000 RBPs encoded within the human genome it is still unclear what role, if any, many of these proteins play during viral replication. Using the RNA interactome capture (RIC) technique, we isolated RBPs from IAV infected cells to unravel the RBPome of mRNAs from IAV infected human cells. This led to the identification of one particular RBP, MKRN2, that associates with and positively regulates IAV mRNA. Through further validation, we determined that MKRN2 is involved in the nuclear-cytoplasmic trafficking of IAV mRNA likely through an association with the RNA export mediator GLE1. In the absence of MKRN2, IAV mRNAs accumulate in the nucleus of infected cells, which we suspect leads to their degradation by the nuclear RNA exosome complex. MKRN2, therefore, appears to be required for the efficient nuclear export of IAV mRNAs in human cells.
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Project description:Dysregulation of proinflammatory cytokine production leads to autoimmune and inflammatory diseases. Although E3 ligases and RNA-binding proteins (RBPs) are critical in autoimmunity and inflammation, whether RNA-binding E3 ligases (E3-RBPs) can regulate proinflammatory cytokine expression to be involved in autoimmune disorders remains unclear. Here, we found that MKRN2, an E3-RBP, selectively inhibits IL-6 expression in LPS-activated macrophages. MKRN2-deficient mice have increased IL-6 serum levels at the untreated stage or after LPS treatment, and exhibit increased severity of experimental colitis which is associated with increased IL-6 levels. MKRN2 is negatively correlated with IL-6 expression in clinical samples from patients with ulcerative colitis and rheumatoid arthritis. Mechanistically, upon encountering Il6 mRNA, MKRN2 links K29 polyubiquitin to Lys179 of PAIP1 which blocks PAIP1-eIF4A interaction, thus inhibiting the translational efficiency of Il6 mRNA. Our findings provide new mechanistic insight and potential therapeutic strategies for inflammatory autoimmune diseases by disrupting translation process of specific proinflammatory cytokines.
2025-04-27 | GSE289945 | GEO
Project description:Dysregulation of proinflammatory cytokine production leads to autoimmune and inflammatory diseases. Although E3 ligases and RNA-binding proteins (RBPs) are critical in autoimmunity and inflammation, whether RNA-binding E3 ligases (E3-RBPs) can regulate proinflammatory cytokine expression to be involved in autoimmune disorders remains unclear. Here, we found that MKRN2, an E3-RBP, selectively inhibits IL-6 expression in LPS-activated macrophages. MKRN2-deficient mice have increased IL-6 serum levels at the untreated stage or after LPS treatment, and exhibit increased severity of experimental colitis which is associated with increased IL-6 levels. MKRN2 is negatively correlated with IL-6 expression in clinical samples from patients with ulcerative colitis and rheumatoid arthritis. Mechanistically, upon encountering Il6 mRNA, MKRN2 links K29 polyubiquitin to Lys179 of PAIP1 which blocks PAIP1-eIF4A interaction, thus inhibiting the translational efficiency of Il6 mRNA. Our findings provide new mechanistic insight and potential therapeutic strategies for inflammatory autoimmune diseases by disrupting translation process of specific proinflammatory cytokines.
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