As the most abundant RNA modification, pseudouridylation has been shown to play critical roles in E. coli, yeast, and humans. However, its function in plants is still unclear. Here, we characterized FCS1, which encodes a pseudouridine synthase in Arabidopsis. fcs1 mutants exhibited severe defects in plant growth, such as delayed development and reduced fertility, and were significantly smaller than the wild type at different developmental stages. FCS1 protein is localized in the mitochondrion. The absence of FCS1 significantly reduces pseudouridylation of mitochondrial 26S rRNA at the U1692 site, which sits in the peptidyl transferase center (PTC). This affection of mitochondrial 26S rRNA may lead to the disruption of mitochondrial translation in the fcs1-1 mutant, causing high accumulation of transcripts but low production of proteins. Dysfunctional mitochondria with abnormal structures were also observed in the fcs1-1 mutant. Overall, our results suggest that FCS1-mediated pseudouridylation of mitochondrial 26S rRNA is required for mitochondrial translation, which is critical for maintaining mitochondrial function and plant development.
Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). However, potential targeted therapies for GBM stem-like cell (GSC) which is responsible for GBM invasion are limited. Herein, we report Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase like Orphan Receptor 1 (ROR1), as a promising target for GSC invasion. Using a GSC-derived brain tumor model, GSCs were characterized into invasive or non-invasive subtypes, and RNA sequencing analysis revealed that IGFBP5 was differentially expressed between these two subtypes. GSC invasion capacity was inhibited by IGFBP5 knockdown and enhanced by IGFBP5 overexpression both in vitro and in vivo, particularly in a patient-derived xenograft model. IGFBP5 binds to ROR1 and facilitates ROR1/HER2 heterodimer formation, followed by inducing CREB-mediated ETV5 and FBXW9 expression, thereby promoting GSC invasion and tumorigenesis. Importantly, using a tumor-specific targeting and penetrating nanocapsule-mediated delivery of CRISPR/Cas9-based IGFBP5 gene editing significantly suppressed GSC invasion and downstream gene expression, and prolonged the survival of orthotopic tumor-bearing mice. Collectively, our data reveal that IGFBP5-ROR1/HER2-CREB signaling axis as a potential GBM therapeutic target.
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