PlumX Metrics
Embed PlumX Metrics

Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase

Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 295, Issue: 10, Page: 3148-3158
2020
  • 2
    Citations
  • 0
    Usage
  • 22
    Captures
  • 1
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    2
    • Citation Indexes
      2
  • Captures
    22
  • Mentions
    1
    • News Mentions
      1
      • 1

Most Recent News

Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu/Zn superoxide dismutase.

J Biol Chem. 2020 Feb 3; Authors: Homma K, Takahashi H, Tsuburaya N, Naguro I, Fujisawa T, Ichijo H PubMed: 32014991 Submit Comment

Article Description

Cu, Zn superoxide dismutase ( SOD1 ) is one of the genes implicated in the devastating neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Although the precise mechanisms of SOD1 mutant (SOD1 mut )-induced motoneuron toxicity are still unclear, defects in SOD1 proteostasis are known to have a critical role in ALS pathogenesis. We previously reported that the SOD1 mut adopts a conformation that exposes a Derlin-1–binding region (DBR) and that DBR-exposed SOD1 interacts with Derlin-1, leading to motoneuron death. We also found that an environmental change, i.e. zinc depletion, induces a conformational change in WT SOD1 (SOD1 WT ) to the DBR-exposed conformation, suggesting the presence of an equilibrium state between the DBR-masked and DBR-exposed states even with SOD1 WT. Here, we conducted a high-throughput screening based on time-resolved FRET to further investigate the SOD1 WT conformational change, and we used a genome-wide siRNA screen to search for regulators of SOD1 proteostasis. This screen yielded 30 candidate genes that maintained an absence of the DBR-exposed SOD1 WT conformation. Among these genes was one encoding DDB1- and CUL4-associated factor 4 (DCAF4), a substrate receptor of the E3 ubiquitin–protein ligase complex. Of note, we found that DCAF4 mediates the ubiquitination of an ALS-associated protein and autophagy receptor, optineurin (OPTN), and facilitates autophagic degradation of DBR-exposed SOD1. In summary, our screen identifies DCAF4 as being required for proper proteostasis of DBR-exposed SOD1, which may have potential relevance for the development of therapies for managing ALS.

Provide Feedback

Have ideas for a new metric? Would you like to see something else here?Let us know