RRC ID 59599
Author Spatola BN, Lo JY, Wang B, Curran SP.
Title Nuclear and cytoplasmic WDR-23 isoforms mediate differential effects on GEN-1 and SKN-1 substrates.
Journal Sci Rep
Abstract Maintaining a healthy cellular environment requires the constant control of proteostasis. E3 ubiquitin ligase complexes facilitate the post-translational addition of ubiquitin, which based on the quantity and specific lysine linkages, results in different outcomes. Our studies reveal the CUL4-DDB1 substrate receptor, WDR23, as both a positive and a negative regulator in cellular stress responses. These opposing roles are mediated by two distinct isoforms: WDR-23A in the cytoplasm and WDR-23B in the nucleus. C. elegans expressing only WDR-23A display activation of SKN-1 and enhanced survival to oxidative stress, whereas animals with restricted WDR-23B expression do not. Additionally, we identify GEN-1, a Holliday junction resolvase, as an evolutionarily conserved WDR-23 substrate and find that the nuclear and cytoplasmic isoforms of WDR-23 differentially affect double-strand break repair. Our results suggest that through differential ubiquitination, nuclear WDR-23B inhibits the activity of substrates, most likely by promoting protein turnover, while cytoplasmic WDR-23A performs a proteasome-independent role. Together, our results establish a cooperative role between two spatially distinct isoforms of WDR-23 in ensuring proper regulation of WDR-23 substrates.
Volume 9(1)
Pages 11783
Published 2019-8-13
DOI 10.1038/s41598-019-48286-y
PII 10.1038/s41598-019-48286-y
PMID 31409866
PMC PMC6692315
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics* Cell Nucleus / genetics* Cytoplasm / genetics DNA-Binding Proteins / genetics* Gene Expression Regulation / genetics Oxidative Stress / genetics Proteolysis Proteostasis / genetics Repressor Proteins / genetics* Substrate Specificity Transcription Factors / genetics* Ubiquitin-Protein Ligases / genetics* Ubiquitination / genetics
IF 4.011
Times Cited 0
C.elegans tm1817 tm2940