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Nuclear and cytoplasmic WDR-23 isoforms mediate differential effects on GEN-1 and SKN-1 substrates

Brett N Spatola1,2, Jacqueline Y Lo1,2,3, Bin Wang4

  • 1University of Southern California, Leonard Davis School of Gerontology, Los Angeles, CA, USA.

Scientific Reports
|August 15, 2019
PubMed

Insights

The WDR23 protein has two forms, WDR-23A and WDR-23B, that regulate cellular stress responses differently. Cytoplasmic WDR-23A enhances stress survival, while nuclear WDR-23B inhibits substrate activity.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Genetics

Background:

  • Proteostasis is crucial for cellular health, involving regulated protein degradation.
  • E3 ubiquitin ligase complexes control protein fate through ubiquitination.
  • WDR23 is a CUL4-DDB1 substrate receptor implicated in cellular regulation.

Purpose of the Study:

  • To investigate the dual role of WDR23 in cellular stress responses.
  • To differentiate the functions of WDR23's cytoplasmic (WDR-23A) and nuclear (WDR-23B) isoforms.
  • To identify WDR-23 substrates and understand their regulation.

Main Methods:

  • Utilized Caenorhabditis elegans models to study WDR23 function.
  • Investigated the impact of distinct WDR23 isoform expression on stress response pathways (e.g., SKN-1 activation).
  • Identified and analyzed WDR-23 substrates, including the Holliday junction resolvase GEN-1, and their role in DNA repair.

Main Results:

  • WDR-23A expression in C. elegans activates SKN-1 and enhances oxidative stress survival.
  • Restricted WDR-23B expression does not confer similar stress resistance.
  • WDR-23 isoforms differentially regulate double-strand break repair, with nuclear WDR-23B likely promoting substrate turnover via ubiquitination and cytoplasmic WDR-23A acting independently of the proteasome.

Conclusions:

  • WDR23 acts as both a positive and negative regulator of cellular stress responses through its distinct isoforms.
  • Nuclear WDR-23B inhibits substrate activity, potentially through proteasomal degradation.
  • Cytoplasmic WDR-23A mediates proteasome-independent functions, contributing to stress adaptation.

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