title: Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation.
abstract: Cleavage of mutant huntingtin (HTT) is an essential process in Huntington's disease (HD), an inherited neurodegenerative disorder. Cleavage generates N-ter fragments that contain the polyQ stretch and whose nuclear toxicity is well established. However, the functional defects induced by cleavage of full-length HTT remain elusive. Moreover, the contribution of non-polyQ C-terminal fragments is unknown. Using time- and site-specific control of full-length HTT proteolysis, we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies. Surprisingly, in addition to the canonical pathogenic N-ter fragments, the C-ter fragments generated, that do not contain the polyQ stretch, induced toxicity via dilation of the endoplasmic reticulum (ER) and increased ER stress. C-ter HTT bound to dynamin 1 and subsequently impaired its activity at ER membranes. Our findings support a role for HTT on dynamin 1 function and ER homoeostasis. Proteolysis-induced alteration of this function may be relevant to disease.
authors.affiliation: Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: El-Daher
authors.affiliation: Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Hangen
authors.affiliation: Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France Inserm U836, Grenoble, France Grenoble Institut des Neurosciences, GIN University of Grenoble Alpes, Grenoble, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bruyère
authors.affiliation: Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Poizat
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.affiliation: Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France.
authors.forename: Raul
authors.initials: R
authors.lastname: Pardo
authors.affiliation: ISMO, CNRS UMR8214 University of Paris Sud, Orsay, France CPBM FR2764 University of Paris Sud, Orsay, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bourg
authors.affiliation: CNRS UMR8122, Villejuif, France Institut Gustave Roussy, Villejuif, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Souquere
authors.affiliation: ISMO, CNRS UMR8214 University of Paris Sud, Orsay, France CPBM FR2764 University of Paris Sud, Orsay, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Mayet
authors.affiliation: CNRS UMR8122, Villejuif, France Institut Gustave Roussy, Villejuif, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.affiliation: ISMO, CNRS UMR8214 University of Paris Sud, Orsay, France CPBM FR2764 University of Paris Sud, Orsay, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lévêque-Fort
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.affiliation: Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France Inserm U836, Grenoble, France Grenoble Institut des Neurosciences, GIN University of Grenoble Alpes, Grenoble, France sandrine.humbert@inserm.fr frederic.saudou@inserm.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
authors.affiliation: Institut Curie, Orsay, France CNRS UMR3306, Orsay, France INSERM U1005, Orsay, France Inserm U836, Grenoble, France Grenoble Institut des Neurosciences, GIN University of Grenoble Alpes, Grenoble, France CHU de Grenoble, Grenoble, France sandrine.humbert@inserm.fr frederic.saudou@inserm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saudou
mesh_terms: D000818:Animals; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D034284:Dynamin I / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C086055:HTT protein, human; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C097188:polyglutamine; D034284:Dynamin I
keywords: Drosophila; ER dilation; Huntington's disease; TEV proteolysis; endoplasmic reticulum