The unexpected role of polyubiquitin chains in the formation of fibrillar aggregates

Daichi Morimoto, Erik Walinda, Harumi Fukada, Yu-Shin Sou, Shun Kageyama, Masaru Hoshino, Takashi Fujii, Hikaru Tsuchiya, Yasushi Saeki, Kyohei Arita, Mariko Ariyoshi, Hidehito Tochio, Kazuhiro Iwai, Keiichi Namba, Masaaki Komatsu, Keiji Tanaka and Masahiro Shirakawa ()
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Daichi Morimoto: Graduate School of Engineering, Kyoto University
Erik Walinda: Graduate School of Engineering, Kyoto University
Harumi Fukada: Graduate School of Life and Environmental Sciences, Osaka Prefecture University
Yu-Shin Sou: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science
Shun Kageyama: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science
Masaru Hoshino: Graduate School of Pharmaceutical Sciences, Kyoto University
Takashi Fujii: Quantitative Biology Center, RIKEN, 1-3 OLABB, Osaka University 6-2-3, Furuedai
Hikaru Tsuchiya: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Yasushi Saeki: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Kyohei Arita: Graduate School of Medical Life Science, Yokohama City University
Mariko Ariyoshi: Graduate School of Engineering, Kyoto University
Hidehito Tochio: Graduate School of Science, Kyoto University
Kazuhiro Iwai: Graduate School of Medicine, Kyoto University
Keiichi Namba: Quantitative Biology Center, RIKEN, 1-3 OLABB, Osaka University 6-2-3, Furuedai
Masaaki Komatsu: Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science
Keiji Tanaka: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Masahiro Shirakawa: Graduate School of Engineering, Kyoto University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7116

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