title: The Ankrd13 Family of Ubiquitin-interacting Motif-bearing Proteins Regulates Valosin-containing Protein/p97 Protein-mediated Lysosomal Trafficking of Caveolin 1.
abstract: Caveolin 1 (Cav-1) is an oligomeric protein that forms flask-shaped, lipid-rich pits, termed caveolae, on the plasma membrane. Cav-1 is targeted for lysosomal degradation in ubiquitination- and valosin-containing protein (VCP)-dependent manners. VCP, an ATPase associated with diverse cellular activities that remodels or segregates ubiquitinated protein complexes, has been proposed to disassemble Cav-1 oligomers on the endosomal membrane, facilitating the trafficking of Cav-1 to the lysosome. Genetic mutations in VCP compromise the lysosomal trafficking of Cav-1, leading to a disease called inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia (IBMPFD). Here we identified the Ankrd13 family of ubiquitin-interacting motif (UIM)-containing proteins as novel VCP-interacting molecules on the endosome. Ankrd13 proteins formed a ternary complex with VCP and Cav-1 and exhibited high binding affinity for ubiquitinated Cav-1 oligomers in an UIM-dependent manner. Mass spectrometric analyses revealed that Cav-1 undergoes Lys-63-linked polyubiquitination, which serves as a lysosomal trafficking signal, and that the UIMs of Ankrd13 proteins bind preferentially to this ubiquitin chain type. The overexpression of Ankrd13 caused enlarged hollow late endosomes, which was reminiscent of the phenotype of the VCP mutations in IBMPFD. Overexpression of Ankrd13 proteins also stabilized ubiquitinated Cav-1 oligomers on the limiting membrane of enlarged endosomes. The interaction with Ankrd13 was abrogated in IMBPFD-associated VCP mutants. Collectively, our results suggest that Ankrd13 proteins cooperate with VCP to regulate the lysosomal trafficking of ubiquitinated Cav-1.
authors.affiliation: From the Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Daocharad
authors.initials: D
authors.lastname: Burana
authors.affiliation: the Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan, and.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Yoshihara
authors.affiliation: From the Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Tanno
authors.affiliation: the Department of Bioscience, Nagahama Institute of Bioscience and Technology, Nagahama 526-0829, Japan.
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: the Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan, and.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: the Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo 156-8506, Japan, and.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: From the Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, Japan, makomada@bio.titech.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D051242:Caveolin 1 / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002522:Chlorocebus aethiops; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D025801:Ubiquitin / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism; D054875:Ubiquitination; D000074405:Valosin Containing Protein
chemical_list: C584194:ANKRD13A protein, human; D051242:Caveolin 1; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D025801:Ubiquitin; D057149:Ubiquitinated Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: VCP/p97; caveolin; cell surface protein; endocytosis; endosome; membrane trafficking; protein degradation; ubiquitin; ubiquitin-interacting motif; ubiquitylation (ubiquitination)