title: Actin-binding protein coronin 1A controls osteoclastic bone resorption by regulating lysosomal secretion of cathepsin K.
abstract: Osteoclasts degrade bone matrix proteins via the secretion of lysosomal enzymes. However, the precise mechanisms by which lysosomal components are transported and fused to the bone-apposed plasma membrane, termed ruffled border membrane, remain elusive. Here, we identified coronin 1A as a negative regulator of exocytotic release of cathepsin K, one of the most important bone-degrading enzymes in osteoclasts. The modulation of coronin 1A expression did not alter osteoclast differentiation and extracellular acidification, but strongly affected the secretion of cathepsin K and osteoclast bone-resorption activity, suggesting the coronin 1A-mediated regulation of lysosomal trafficking and protease exocytosis. Further analyses suggested that coronin 1A prevented the lipidation-mediated sorting of the autophagy-related protein LC3 to the ruffled border and attenuated lysosome-plasma membrane fusion. In this process, the interactions between coronin 1A and actin were crucial. Collectively, our findings indicate that coronin 1A is a pivotal component that regulates lysosomal fusion and the secretion pathway in osteoclast-lineage cells and may provide a novel therapeutic target for bone diseases.
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.|Department of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Ohmae
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Naruto
authors.initials: N
authors.lastname: Noma
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Toyomoto
authors.affiliation: Department of Systems BioMedicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.|PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeiri
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.|Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fuji
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.|Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takemoto
authors.affiliation: Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Fujita
authors.affiliation: PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.|Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.affiliation: Chemical Biology Research Group, RIKEN CSRS, Wako, Saitama, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawatani
authors.affiliation: Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Mineyoshi
authors.initials: M
authors.lastname: Aoyama
authors.affiliation: Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
authors.affiliation: Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishihama
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.|Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.|Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056657:Cathepsin K / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D000199:Actins; D008840:Microfilament Proteins; D053245:RANK Ligand; C072061:coronin proteins; D056657:Cathepsin K