Quaking isoforms cooperate to promote the mesenchymal phenotype

The RNA-binding protein Quaking (QKI) has widespread effects on mRNA regulation including alternative splicing, stability, translation, and localization of target mRNAs. Recently, QKI was found to be induced during epithelial-mesenchymal transition (EMT), where it promotes a mesenchymal alternative...

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Bibliographic Details
Published in:Molecular biology of the cell 2024-02, Vol.35 (2), p.ar17-ar17
Main Authors: Neumann, Daniel P, Phillips, Caroline A, Lumb, Rachael, Palethorpe, Helen M, Ramani, Yesha, Hollier, Brett G, Selth, Luke A, Bracken, Cameron P, Goodall, Gregory J, Gregory, Philip A
Format: Article
Language:English
Subjects:
Alternative Splicing
Analysis
Binding proteins
Humans
Identification and classification
Phenotype
Properties
Protein Isoforms - metabolism
RNA
RNA Splicing
RNA, Messenger - genetics
RNA, Messenger - metabolism
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Summary:The RNA-binding protein Quaking (QKI) has widespread effects on mRNA regulation including alternative splicing, stability, translation, and localization of target mRNAs. Recently, QKI was found to be induced during epithelial-mesenchymal transition (EMT), where it promotes a mesenchymal alternative splicing signature that contributes to the mesenchymal phenotype. QKI is itself alternatively spliced to produce three major isoforms, QKI-5, QKI-6, and QKI-7. While QKI-5 is primarily localized to the nucleus where it controls mesenchymal splicing during EMT, the functions of the two predominantly cytoplasmic isoforms, QKI-6 and QKI-7, in this context remain uncharacterized. Here we used CRISPR-mediated depletion of QKI in a human mammary epithelial cell model of EMT and studied the effects of expressing the QKI isoforms in isolation and in combination. QKI-5 was required to induce mesenchymal morphology, while combined expression of QKI-5 with either QKI-6 or QKI-7 further enhanced mesenchymal morphology and cell migration. In addition, we found that QKI-6 and QKI-7 can partially localize to the nucleus and contribute to alternative splicing of QKI target genes. These findings indicate that the QKI isoforms function in a dynamic and cooperative manner to promote the mesenchymal phenotype.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E23-08-0316