title: Developmentally Regulated RNA-binding Protein 1 (Drb1)/RNA-binding Motif Protein 45 (RBM45), a Nuclear-Cytoplasmic Trafficking Protein, Forms TAR DNA-binding Protein 43 (TDP-43)-mediated Cytoplasmic Aggregates.
abstract: Cytoplasmic protein aggregates are one of the pathological hallmarks of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Several RNA-binding proteins have been identified as components of inclusion bodies. Developmentally regulated RNA-binding protein 1 (Drb1)/RNA-binding motif protein 45 is an RNA-binding protein that was recently described as a component in ALS- and FTLD-related inclusion bodies. However, the molecular mechanism underlying cytoplasmic Drb1 aggregation remains unclear. Here, using an in vitro cellular model, we demonstrated that Drb1 co-localizes with cytoplasmic aggregates mediated by TAR DNA-binding protein 43, a major component of ALS and FTLD-related inclusion bodies. We also defined the domains involved in the subcellular localization of Drb1 to clarify the role of Drb1 in the formation of cytoplasmic aggregates in ALS and FTLD. Drb1 predominantly localized in the nucleus via a classical nuclear localization signal in its carboxyl terminus and is a shuttling protein between the nucleus and cytoplasm. Furthermore, we identify a double leucine motif serving as a nuclear export signal. The Drb1 mutant, presenting mutations in both nuclear localization signal and nuclear export signal, is prone to aggregate in the cytoplasm. The mutant Drb1-induced cytoplasmic aggregates not only recruit TAR DNA-binding protein 43 but also decrease the mitochondrial membrane potential. Taken together, these results indicate that perturbation of Drb1 nuclear-cytoplasmic trafficking induces toxic cytoplasmic aggregates, suggesting that mislocalization of Drb1 is involved in the cause of cytotoxicity in neuronal cells.
authors.affiliation: From the Departments of Biochemistry and Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mashiko
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sakashita
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Kasashima
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tominaga
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuroiwa
authors.affiliation: Pediatrics and.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Matsuura
authors.affiliation: From the Departments of Biochemistry and.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hamamoto
authors.affiliation: From the Departments of Biochemistry and hendo@jichi.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endo
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D049790:Nuclear Export Signals / Q000235:genetics; D019913:Nuclear Localization Signals / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; C467044:RBM45 protein, human; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C000598624:TARDBP protein, human
keywords: ALS (Lou Gehrig disease); RNA binding protein; TAR DNA-binding protein 43 (TDP-43, TARDBP); cytoplasmic inclusion body; frontotemporal lobar degeneration (FTLD); neurodegenerative disease; nuclear-cytoplasmic trafficking; protein aggregation