title: An N-terminal nuclear export signal regulates trafficking and aggregation of Huntingtin (Htt) protein exon 1.
abstract: Huntington disease is a dominantly inherited neurodegenerative condition caused by polyglutamine expansion in the N terminus of the huntingtin protein (Htt). The first 17 amino acids (N17) of Htt play a key role in regulating its toxicity and aggregation. Both nuclear export and cytoplasm retention functions have been ascribed to N17. We have determined that N17 acts as a nuclear export sequence (NES) within Htt exon and when fused to yellow fluorescent protein. We have defined amino acids within N17 that constitute the nuclear export sequence (NES). Mutation of any of the conserved residues increases nuclear accumulation of Htt exon 1. Nuclear export of Htt is sensitive to leptomycin B and is reduced by knockdown of exportin 1. In HEK293 cells, NES mutations decrease overall Htt aggregation but increase the fraction of cells with nuclear inclusions. In primary cultured neurons, NES mutations increase nuclear accumulation and increase overall aggregation. This work defines a bona fide nuclear export sequence within N17 and links it to effects on protein aggregation. This may help explain the important role of N17 in controlling Htt toxicity.
authors: Department of Neurology, Washington University, St Louis, Missouri 63110, USA.
authors: Zhiqiang
authors: Z
authors: Zheng
authors: Aimin
authors: A
authors: Li
authors: Brandon B
authors: BB
authors: Holmes
authors: Jayne C
authors: JC
authors: Marasa
authors: Marc I
authors: MI
authors: Diamond
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D000903:Antibiotics, Antineoplastic; D005231:Fatty Acids, Unsaturated; D000071058:Huntingtin Protein; D028884:Karyopherins; D009419:Nerve Tissue Proteins; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C086055:HTT protein, human; C038753:leptomycin B