The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans.

Choe KP, Przybysz AJ, Strange K
Mol Cell Biol. 2009 29 (10): 2704-15

PMID: 19273594 · PMCID: PMC2682033 · DOI:10.1128/MCB.01811-08

The transcription factor SKN-1 protects Caenorhabditis elegans from stress and promotes longevity. SKN-1 is regulated by diverse signals that control metabolism, development, and stress responses, but the mechanisms of regulation and signal integration are unknown. We screened the C. elegans genome for regulators of cytoprotective gene expression and identified a new SKN-1 regulatory pathway. SKN-1 protein levels, nuclear accumulation, and activity are repressed by the WD40 repeat protein WDR-23, which interacts with the CUL-4/DDB-1 ubiquitin ligase to presumably target the transcription factor for proteasomal degradation. WDR-23 regulates SKN-1 target genes downstream from p38 mitogen-activated protein kinase, glycogen synthase kinase 3, and insulin-like receptor pathways, suggesting that phosphorylation of SKN-1 may function to modify its interaction with WDR-23 and/or CUL-4/DDB-1. These findings define the mechanism of SKN-1 accumulation in the cell nucleus and provide a new mechanistic framework for understanding how phosphorylation signals are integrated to regulate stress resistance and longevity.

MeSH Terms (25)

Amino Acid Sequence Animals Caenorhabditis elegans Caenorhabditis elegans Proteins Cell Nucleus Cullin Proteins DNA-Binding Proteins Forkhead Transcription Factors Gene Expression Regulation Glutathione Transferase Humans Isoenzymes MAP Kinase Kinase 4 Molecular Sequence Data Phylogeny Proteasome Endopeptidase Complex Receptor, Insulin Recombinant Fusion Proteins Repetitive Sequences, Amino Acid Repressor Proteins Sequence Alignment Signal Transduction Stress, Physiological Transcription Factors Two-Hybrid System Techniques

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