Ubiquitin-Binding Protein CG5445 Suppresses Aggregation and Cytotoxicity of Amyotrophic Lateral Sclerosis-Linked TDP-43 in Drosophila

Mol Cell Biol. 2018 Jan 16;38(3):e00195-17. doi: 10.1128/MCB.00195-17. Print 2018 Feb 1.

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.

Keywords: protein homeostasis; ubiquitin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Animals, Genetically Modified
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Eye / pathology
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H / metabolism
  • Mutation
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Solubility
  • Ubiquitin / metabolism
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • CG5445 protein, Drosophila
  • DNA-Binding Proteins
  • Drosophila Proteins
  • FUS protein, Drosophila
  • Heterogeneous-Nuclear Ribonucleoprotein Group F-H
  • TBPH protein, Drosophila
  • Ubiquitin
  • Proteasome Endopeptidase Complex