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

Huntingtin protein, mutated in Huntington's disease, is implicated in nucleic acid-mediated processes, yet the evidence for direct huntingtin-nucleic acid interaction is limited. Here, we show wild-type and mutant huntingtin copurify 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 wild-type and mutant huntingtin revealed long noncoding RNA as a significantly enriched transcript. Altered levels were evident in Huntington's disease cells and postmortem brain tissues, and huntingtin knockdown decreased levels. Huntingtin colocalized with in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights as a huntingtin interactor, demonstrating huntingtin's involvement in RNA-mediated functions and paraspeckle regulation.