Ubiquitin-binding protein CG5445 suppresses aggregation and cytotoxicity of amyotrophic lateral sclerosis-linked TDP-43 in Drosophila

Hiroyuki Uechi, Erina Kuranaga, Tomohiro Iriki, Kohei Takano, Shoshiro Hirayama, Masayuki Miura, Jun Hamazaki, Shigeo Murata

    研究成果: Article査読

    7 被引用数 (Scopus)

    抄録

    Ubiquitin-mediated protein degradation plays essential roles in proteostasis and is involved in the pathogenesis of neurodegenerative diseases in which ubiquitin-positive aberrant proteins accumulate. However, how such aberrant proteins are processed inside cells has not been fully explored. Here, we show that the product of CG5445, a previously uncharacterized Drosophila gene, prevents the accumulation of aggregate-prone ubiquitinated proteins. We found that ubiquitin conjugates were associated with CG5445, the knockdown of which caused the accumulation of detergent-insoluble ubiquitinated proteins. Furthermore, CG5445 rescued eye degeneration caused by the amyotrophic lateral sclerosis (ALS)-linked mutant TAR DNA-binding protein of 43 kDa (TDP-43), which often forms ubiquitin-positive aggregates in cells through the capacity of CG5445 to bind to ubiquitin chains. Biochemically, CG5445 inhibited the accumulation of insoluble forms and promoted their clearance. Our results demonstrate a new possible mechanism by which cells maintain ubiquitinated aggregation-prone proteins in a soluble form to decrease their cytotoxicity until they are degraded.

    本文言語English
    論文番号e00195-17
    ジャーナルMolecular and cellular biology
    38
    3
    DOI
    出版ステータスPublished - 2018 2月 1

    ASJC Scopus subject areas

    • 分子生物学
    • 細胞生物学

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