Huntingtin is an RNA-binding protein and participates in NEAT1-mediated paraspeckles

Yadav, M.; Harding, R. J.; Li, T.; Xu, X.; Gall-Duncan, T.; Khan, M.; Ferrari Bardile, C.; Sequiera, G. L.; Duan, S.; Chandrasekaran, R.; Pan, A.; Bu, J.; Yamazaki, T.; Hirose, T.; Prinos, P.; Tippett, L.; Turner, C.; Curtis, M. A.; Faull, R. L. M.; Pouladi, M. A.; Pearson, C. E.; He, H. H.; Arrowsmith, C. H.

doi:10.1101/2024.02.07.579162

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bioRxiv · 10.1101/2024.02.07.579162

Huntingtin is an RNA-binding protein and participates in NEAT1-mediated paraspeckles

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Abstract

AbstractHuntingtin protein, mutated in Huntington disease, is implicated in nucleic acid- mediated processes, yet evidence for direct huntingtin-nucleic acid interaction is limited. Here we show wildtype and mutant huntingtin co-purify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wildtype and mutant huntingtin revealed NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntingtons disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin co-localized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a novel huntingtin interactor, demonstrating huntingtins involvement in RNA-mediated functions and paraspeckle regulation. One-Sentence SummaryHTT is an RNA-binding protein that interacts with G-rich sequences, including those in the paraspeckle lncRNA NEAT1.

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Yadav, M., Harding, R. J., Li, T., Xu, X., Gall-Duncan, T., Khan, M., Ferrari Bardile, C., Sequiera, G. L., Duan, S., Chandrasekaran, R., Pan, A., Bu, J., Yamazaki, T., Hirose, T., Prinos, P., Tippett, L., Turner, C., Curtis, M. A., Faull, R. L. M., Pouladi, M. A., Pearson, C. E., He, H. H., Arrowsmith, C. H.. 2024-02-08. Huntingtin is an RNA-binding protein and participates in NEAT1-mediated paraspeckles. https://doi.org/10.1101/2024.02.07.579162

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