title: The unexpected role of polyubiquitin chains in the formation of fibrillar aggregates.
abstract: Ubiquitin is known to be one of the most soluble and stably folded intracellular proteins, but it is often found in inclusion bodies associated with various diseases including neurodegenerative disorders and cancer. To gain insight into this contradictory behaviour, we have examined the physicochemical properties of ubiquitin and its polymeric chains that lead to aggregate formation. We find that the folding stability of ubiquitin chains unexpectedly decreases with increasing chain length, resulting in the formation of amyloid-like fibrils. Furthermore, when expressed in cells, polyubiquitin chains covalently linked to EGFP also form aggregates depending on chain length. Notably, these aggregates are selectively degraded by autophagy. We propose a novel model in which the physical and chemical instability of polyubiquitin chains drives the formation of fibrils, which then serve as an initiation signal for autophagy.
authors.affiliation: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Morimoto
authors.affiliation: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
authors.forename: Erik
authors.initials: E
authors.lastname: Walinda
authors.affiliation: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Fukada
authors.affiliation: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Sou
authors.affiliation: 1] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Department of Biochemistry, School of Medicine, Niigata University, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Kageyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Hoshino
authors.affiliation: Quantitative Biology Center, RIKEN, 1-3 OLABB, Osaka University 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Tsuchiya
authors.affiliation: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Saeki
authors.affiliation: Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Arita
authors.affiliation: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ariyoshi
authors.affiliation: Department of Biophysics, Graduate School of Science, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-Ku, Kyoto 606-8502, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Tochio
authors.affiliation: Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.affiliation: 1] Quantitative Biology Center, RIKEN, 1-3 OLABB, Osaka University 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan [2] Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Namba
authors.affiliation: 1] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Department of Biochemistry, School of Medicine, Niigata University, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shirakawa
mesh_terms: D000818:Animals; D001343:Autophagy; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D004926:Escherichia coli / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D046529:Microscopy, Electron, Transmission; D025821:Polyubiquitin / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D061987:Sf9 Cells; D013050:Spectrometry, Fluorescence; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D025821:Polyubiquitin