title: Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane.
abstract: Huntingtin is a large membrane-associated scaffolding protein that associates with endocytic and exocytic vesicles and modulates their trafficking along cytoskeletal tracks. Although the progression of Huntington's disease is linked to toxic accumulation of mutant huntingtin protein, loss of wild-type huntingtin function might also contribute to neuronal cell death, but its precise function is not well understood. Therefore, we investigated the molecular role of huntingtin in exocytosis and observed that huntingtin knockdown in HeLa cells causes a delay in endoplasmic reticulum (ER)-to-Golgi transport and a reduction in the number of cargo vesicles leaving the trans-Golgi network. In addition, we found that huntingtin is required for secretory vesicle fusion at the plasma membrane. Similar defects in the early exocytic pathway were observed in primary fibroblasts from homozygous Htt(140Q/140Q) knock-in mice, which have the expansion inserted into the mouse huntingtin gene so lack wild-type huntingtin expression. Interestingly, heterozygous fibroblasts from a Huntington's disease patient with a 180Q expansion displayed no obvious defects in the early secretory pathway. Thus, our results highlight the requirement for wild-type huntingtin at distinct steps along the secretory pathway.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Hemma
authors.initials: H
authors.lastname: Brandstaetter
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: Antonina J
authors.initials: AJ
authors.lastname: Kruppa
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK. fb207@cam.ac.uk.
authors.forename: Folma
authors.initials: F
authors.lastname: Buss
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease; D051379:Mice; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins
keywords: ER; Exocytosis; Golgi; Huntingtin; Vesicle fusion