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

    Research output: Contribution to journalArticlepeer-review

    6 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Article numbere00195-17
    JournalMolecular and cellular biology
    Volume38
    Issue number3
    DOIs
    Publication statusPublished - 2018 Feb 1

    Keywords

    • Protein homeostasis
    • Ubiquitin

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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