title: Identification of NUB1 as a suppressor of mutant Huntington toxicity via enhanced protein clearance.
abstract: Huntington's disease is caused by expanded CAG repeats in HTT, conferring toxic gain of function on mutant HTT (mHTT) protein. Reducing mHTT amounts is postulated as a strategy for therapeutic intervention. We conducted genome-wide RNA interference screens for genes modifying mHTT abundance and identified 13 hits. We tested 10 in vivo in a Drosophila melanogaster Huntington's disease model, and 6 exhibited activity consistent with the in vitro screening results. Among these, negative regulator of ubiquitin-like protein 1 (NUB1) overexpression lowered mHTT in neuronal models and rescued mHTT-induced death. NUB1 reduces mHTT amounts by enhancing polyubiquitination and proteasomal degradation of mHTT protein. The process requires CUL3 and the ubiquitin-like protein NEDD8 necessary for CUL3 activation. As a potential approach to modulating NUB1 for treatment, interferon-β lowered mHTT and rescued neuronal toxicity through induction of NUB1. Thus, we have identified genes modifying endogenous mHTT using high-throughput screening and demonstrate NUB1 as an exemplar entry point for therapeutic intervention of Huntington's disease.
authors.affiliation: School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Boxun
authors.initials: B
authors.lastname: Lu
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.forename: Antonio
authors.initials: A
authors.lastname: Valencia
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: Frada
authors.initials: F
authors.lastname: Berenshteyn
authors.forename: Haidi
authors.initials: H
authors.lastname: Yang
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gallego-Flores
authors.forename: Salah
authors.initials: S
authors.lastname: Ichcho
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lacoste
authors.forename: Marc
authors.initials: M
authors.lastname: Hild
authors.forename: Marian
authors.initials: M
authors.lastname: Difiglia
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.forename: James
authors.initials: J
authors.lastname: Palacino
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000187:drug effects / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D000075687:NEDD8 Protein; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D044842:Cullin Proteins; C512253:FAT10 protein, mouse; C086055:HTT protein, human; D000071058:Huntingtin Protein; D000075687:NEDD8 Protein; C430242:NUB1 protein, human; C513172:Nedd8 protein, mouse; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D014452:Ubiquitins; D000255:Adenosine Triphosphate