ArticleHuman molecular genetics2013
The huntingtin N17 domain is a multifunctional CRM1 and Ran-dependent nuclear and cilial export signal.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 132 citations in OpenAlex.
- Prevention of ubiquitination at K6 and K9 in mutant huntingtin exacerbates disease pathology in a knock-in mouse model.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases.Biology · 2025Review
- Opposing roles for GSK3β and ERK1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington's disease.Cell death & disease · 2025Article
- Regulation of Mutant Huntingtin Mitochondrial Toxicity by Phosphomimetic Mutations within Its N-Terminal Region.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease.Neurobiology of disease · 2025Article
- Poly ADP-ribose signaling is dysregulated in Huntington disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Huntingtin is an RNA binding protein and participates inScience advances · 2024Article
- Fluorescent protein tagging promotes phase separation and alters the aggregation pathway of huntingtin exon-1.The Journal of biological chemistry · 2024Article
- The N17 domain of huntingtin as a multifaceted player in Huntington's disease.Frontiers in molecular biosciences · 2024Review
- IKBKB reduces huntingtin aggregation by phosphorylating serine 13 via a non-canonical IKK pathway.Life science alliance · 2023Article
- Huntingtin Interacting Proteins and Pathological Implications.International journal of molecular sciences · 2023Review
- Ubiquitin-modifying enzymes in Huntington's disease.Frontiers in molecular biosciences · 2023Review
- HSF1 and Its Role in Huntington's Disease Pathology.Advances in experimental medicine and biology · 2023Review
- Gene Alterations Induced by Glutamine (Q) Encoding CAG Repeats Associated with Neurodegeneration.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Protein Kinase CK2 and Its Potential Role as a Therapeutic Target in Huntington's Disease.Biomedicines · 2022Review
- Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes.Biochemistry · 2022Article
- Recent Microscopy Advances and the Applications to Huntington's Disease Research.Journal of Huntington's disease · 2022Review
- Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington's Disease.Journal of Huntington's disease · 2022Article
- Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1.Communications biology · 2021Article
- Karyopherin abnormalities in neurodegenerative proteinopathies.Brain : a journal of neurology · 2021Review
13 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The first 17 amino acids of Huntington's disease (HD) protein, huntingtin, comprise an amphipathic alpha-helical domain that can target huntingtin to the endoplasmic reticulum (ER). N17 is phosphorylated at two serines, shown to be important for disease development in genetic mouse models, and shown to be modified by agents that reverse the disease phenotype in an HD mouse model. Here, we show that the hydrophobic face of N17 comprises a consensus CRM1/exportin-dependent nuclear export signal, and that this nuclear export activity can be affected by serine phospho-mimetic mutants. We define the precise residues that comprise this nuclear export sequence (NES) as well as the interaction of the NES, but not phospho-mimetic mutants, with the CRM1 nuclear export factor. We show that the nuclear localization of huntingtin depends upon the RanGTP/GDP gradient, and that N17 phosphorylation can also distinguish localization of endogenous huntingtin between the basal body and stalk of the primary cilium. We present a mechanism and multifunctional role for N17 in which phosphorylation of N17 not only releases huntingtin from the ER to allow nuclear entry, but also prevents nuclear export during a transient stress response event to increase the levels of nuclear huntingtin and to regulate huntingtin access to the primary cilium. Thus, N17 is a master localization signal of huntingtin that can mediate huntingtin localization between the cytoplasm, nucleus and primary cilium. This localization can be regulated by signaling, and is misregulated in HD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.