title: Nuclear localization of MBNL1: splicing-mediated autoregulation and repression of repeat-derived aberrant proteins.
abstract: In some neurological diseases caused by repeat expansions such as myotonic dystrophy, the RNA-binding protein muscleblind-like 1 (MBNL1) accumulates in intranuclear inclusions containing mutant repeat RNA. The interaction between MBNL1 and mutant RNA in the nucleus is a key event leading to loss of MBNL function, yet the details of this effect have been elusive. Here, we investigated the mechanism and significance of MBNL1 nuclear localization. We found that MBNL1 contains two classes of nuclear localization signal (NLS), a classical bipartite NLS and a novel conformational NLS. Alternative splicing of exon 7 acts as a switch between these NLS types and couples MBNL1 activity and intracellular localization. Depending on its nuclear localization, MBNL1 promoted nuclear accumulation of mutant RNA containing a CUG or CAG repeat, some of which produced proteins containing homopolymeric tracts such as polyglutamine. Furthermore, MBNL1 repressed the expression of these homopolymeric proteins including those presumably produced through repeat-associated non-ATG (RAN) translation. These results suggest that nuclear retention of expanded RNA reflects a novel role of MBNL proteins in repressing aberrant protein expression and may provide pathological and therapeutic implications for a wide range of repeat expansion diseases associated with nuclear RNA retention and/or RAN translation.
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan CREST (Core Research for Evolutionary Science and Technology), JST, Saitama 332-0012, Japan Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama 351-0198, Japan Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo 204-8588, Japan and.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.affiliation: Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama 351-0198, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Washizu
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan CREST (Core Research for Evolutionary Science and Technology), JST, Saitama 332-0012, Japan Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama 351-0198, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, the University of Tokyo, Tokyo 153-8902, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Oma
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, the University of Tokyo, Tokyo 153-8902, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-0033, Japan CREST (Core Research for Evolutionary Science and Technology), JST, Saitama 332-0012, Japan Laboratory for Structural Neuropathology, Brain Science Institute, RIKEN, Saitama 351-0198, Japan nnukina@juntendo.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: D004268:DNA-Binding Proteins; C493663:MBNL1 protein, human; C479922:Mbnl1 protein, mouse; D019913:Nuclear Localization Signals; D012333:RNA, Messenger; D016601:RNA-Binding Proteins