Transcriptional response to loss of rab-11.1
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE189106 | GEO | 2022/01/28
REPOSITORIES: GEO
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Project description:Transcriptional response to loss of rab-11.1
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Project description:In mammals, RNA interference (RNAi) is mostly studied as a cytoplasmic event, however, numerous reports convincingly show nuclear localization of the AGO proteins. Nevertheless, the mechanism of nuclear entry remains to be fully elucidated, and the extent of nuclear RNAi further explored. We found that reduced Lamin A levels significantly induced nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cell lines, which normally have no nuclear AGO2. The translocation of AGO2 was accompanied by aggravated cell proliferation and we further found that the loss of Lamin A leads to EGFR and Src kinase activation, which regulates the turnover and stability of cytoplasmic AGO2. Furthermore, Lamin A KO significantly reduced the activity of nuclear RNAi. This was evident by AGO fPAR-CLIP in WT and Lamin A KO cells, where we observed ca 60% less efficiency of RNAi. Mass spectrometry of AGO interactome, from the nuclear fraction, indicated that AGO2 is in complex with FAM120A, a known interactor of AGO2 that reduces the activity of RNAi by competing with AGO2 transcript binding. Therefore, loss of Lamin A starts a signaling cascade that mediates nuclear AGO2 translocation to rapidly inhibit RNAi in order to facilitate cancer proliferation
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Project description:In mammals, RNA interference (RNAi) is mostly studied as a cytoplasmic event, however, numerous reports convincingly showed nuclear localization of AGO proteins. Nevertheless, the mechanism of the nuclear entry remains to be fully elucidated, and the extent of nuclear RNAi explored. The nuclear import of large proteins requires active transport through the nuclear envelope (NE). Therefore, we hypothesized that the NE, and its composition, is important for nuclear AGO2 translocation. Lamin A knockout significantly induced nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cells. We unravelled that the loss of Lamin A leads to EGFR and Src kinase activation, which regulates the turnover and stability of cytoplasmic specifically AGO2. Furthermore, EGFR mediated phosphorylation at Y393 inhibits the activity of nuclear RNAi. This was evident by AGO fPAR-CLIP in WT and KO cells, where we observed a decrease in RNAi potential. Mass spectrometry of AGO interactome, from the nuclear fraction, indicated that AGO2 is in complex with FAM120A, which may further reduced the activity of RNAi by competing with AGO2 transcript binding. Therefore, loss of Lamin A starts a signalling cascade that mediates nuclear AGO2 translocation to rapidly inhibit RNAi.
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Project description:Rab and associated effector proteins are involved in all steps of cargo transport through subcellular compartments during the endocytic pathway that participates in multiple cellular processes including signal transduction, protein recycling and degradation. We identified Rabgef1 (also called Rabex-5) as the only differentially expressed Rab-associated gene that exhibits strong concordance with photoreceptor maturation by mining the retinal transcriptome data. The retinas of Rabgef1-/- mice exhibit defects in photoreceptor morphology, followed by cell death, and almost complete loss of both rod and cone photoreceptor function within 3 weeks after birth. Like other cells/tissues, Rabgef1 interacts with Rabaptin5 in the retina and its loss leads to reduced early endosomes in the photoreceptor inner segments as indicated by EEA1 immunostaining. Rabgef1-/- photoreceptors abnormally accumulate autophagosomes, and proteomic profiling of endosome-enriched fractions demonstrate significant depletion of phototransduction and mitochondrial proteins. Transcriptome analysis of developing retina before the degeneration is evident reveals energy metabolism modules and gene regulatory landscape that likely suggest the trajectory of cellular changes leading to photoreceptor degeneration. Our results directly implicate endocytic pathway in outer segment biogenesis and photoreceptor development and provide strong evidence that endocytosis defects in the retina can trigger upregulation of autophagic mechanisms. We also suggest that Rabgef1 and components of the endocytic and autophagic pathways should be considered as candidates for human retinopathies.
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Project description:In mammals, RNA interference (RNAi) was historically studied as a cytoplasmic event, however, in the last decade growing number of reports convincingly show nuclear localization of the AGO proteins. Nevertheless, the mechanism and the extent of nuclear RNAi remains to be fully elucidated. We found that reduced Lamin A levels significantly induced nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cell lines, which normally have no nuclear AGO2. Lamin A KO manifested a more pronounced effect in SHSY5Y cells compared to A375 evident by changes in cell morphology, increased cell proliferation and oncogenic miRNA expression. Furthermore, in SHSY5Y cells, AGO fPAR-CLIP in Lamin A KO cells revealed significantly reduced activity of RNAi. Further exploration of the nuclear AGO interactome by mass spectrometry indicated that AGO2 is in complex with FAM120A, an RNA binding protein and known interactor of AGO2. By performing FAM120A fPAR-CLIP we discovered that FAM120A co-binds AGO targets and that this competition reduces the activity of RNAi. Therefore, loss of Lamin A triggers nuclear AGO2 translocation, RNAi impairment and selective upregulation of oncogenic miRNAs to facilitate cancer cell proliferation.
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Project description:In mammals, RNA interference (RNAi) was historically studied as a cytoplasmic event, however, in the last decade growing number of reports convincingly show nuclear localization of the AGO proteins. Nevertheless, the mechanism and the extent of nuclear RNAi remains to be fully elucidated. We found that reduced Lamin A levels significantly induced nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cell lines, which normally have no nuclear AGO2. Lamin A KO manifested a more pronounced effect in SHSY5Y cells compared to A375 evident by changes in cell morphology, increased cell proliferation and oncogenic miRNA expression. Furthermore, in SHSY5Y cells, AGO fPAR-CLIP in Lamin A KO cells revealed significantly reduced activity of RNAi. Further exploration of the nuclear AGO interactome by mass spectrometry indicated that AGO2 is in complex with FAM120A, an RNA binding protein and known interactor of AGO2. By performing FAM120A fPAR-CLIP we discovered that FAM120A co-binds AGO targets and that this competition reduces the activity of RNAi. Therefore, loss of Lamin A triggers nuclear AGO2 translocation, RNAi impairment and selective upregulation of oncogenic miRNAs to facilitate cancer cell proliferation.
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