title: Proteasome inhibition induces inclusion bodies associated with intermediate filaments and fragmentation of the Golgi apparatus.
abstract: The ubiquitin-proteasome system is involved in a variety of biological processes. Inclusion bodies associated with intermediate filaments (IFs) and ubiquitin are observed in various diseases; however, the precise mechanisms of formation and the pathological significance of inclusion bodies have not been fully understood. We examined the effect of proteasome inhibitors on the structure of IF using anti-cytokeratin antibodies or transfection of green fluorescent protein-fused cytokeratin 18 in a hepatoma cell line, Huh7. Intracellular organelles were visualized by immunofluorescent and electron microscopies. Proteasome inhibitors induced IF inclusions associated with ubiquitin. Electron microscopic examination revealed inclusion bodies surrounded by filamentous structures. Autophagic vacuoles and lysosomes were frequently observed, and the organization of the Golgi apparatus was disrupted in these cells. After the removal of the proteasome inhibitors, the IF network and organization of the Golgi apparatus were restored. The IF inclusions could be induced by inhibition of the proteasome function. IF inclusions induced fragmentation of the Golgi apparatus and might inhibit the function of this important station of membrane traffic. The IF inclusions disappeared by restoring proteasome function, and autophagy and lysosomal degradation might be, at least in part, associated with the elimination of inclusion bodies.
authors.affiliation: Second Department of Medicine and Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. harada@med.kurume-u.ac.jp
authors.forename: Masaru
authors.initials: M
authors.lastname: Harada
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kumemura
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Noriko
authors.initials: N
authors.lastname: Maeyama
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hanada
authors.forename: Eitaro
authors.initials: E
authors.lastname: Taniguchi
authors.forename: Hironori
authors.initials: H
authors.lastname: Koga
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Suganuma
authors.forename: Takato
authors.initials: T
authors.lastname: Ueno
authors.forename: Michio
authors.initials: M
authors.lastname: Sata
mesh_terms: D001343:Autophagy; D003546:Cysteine Endopeptidases; D006056:Golgi Apparatus / Q000187:drug effects* / Q000648:ultrastructure; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects*; D007382:Intermediate Filaments / Q000187:drug effects* / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D014407:Tumor Cells, Cultured
chemical_list: D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex