Identification of Potential RIDD Target Genes Using Subcellular RNA-seq
RIDD(regulated inositol-requiring enzyme 1 dependent RNA decay)is one of manifestations of the RNase activity of the endoplasmic reticulum stress sensor IRE 1(inositol-requiring enzyme 1).RIDD plays a critical role in modulating cell fate and is intri-cately involved in regulating various cellular processes including differentiation,lipid and glucose metabolism,and inflammation.Thus,elucidating the repertoire of RIDD target genes and their physiological implications holds significance for understanding disease mechanisms,identifying novel therapeutic targets,and advancing therapeutic strategies.However,existing studies on RIDD target genes face several challenges,leaving numerous potential targets undiscovered.In this study,leveraging subcellular RNA-seq,we es-tablished three criteria for screening potential RIDD target genes:(1)genes exhibiting specific down-regulation in the cytoplasm follow-ing endoplasmic reticulum stress;(2)genes enriched in the cytoplasmic face of endoplasmic reticulum membranes;and(3)genes with a consistent CUGCAG sequence motif on mRNA,which could form stable stem-loop structures.Consequently,our analysis identified 128 genes as potential RIDD targets.Notably,our study uniquely emphasizes the sequence-dependent RNA decay occurring on the cy-toplasmic face of endoplasmic reticulum membranes,while mitigating confounding factors such as changes in transcriptional levels and alternative RNA decay pathways.Besides their involvement in cell division pathways,our findings link these potential RIDD targets to the Wnt(wingless-related integration site)signaling pathway.This finding helps to elucidate the mechanism that how endoplasmic re-ticulum stress regulates Wnt signaling pathway,and opens up new avenues for treating cancers driven by abnormal Wnt activity.
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