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Molecular and Cellular Biology, May 2009, p. 2704-2715, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01811-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Keith P. Choe,1*,{dagger} Aaron J. Przybysz,2,{dagger} and Kevin Strange1

Departments of Molecular Physiology and Biophysics,1 Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 372322

Received 26 November 2008/ Returned for modification 8 January 2009/ Accepted 25 February 2009

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.

* Corresponding author. Mailing address: Vanderbilt University Medical Center, T-4208 Medical Center North, Nashville, TN 37232-2520. Phone: (615) 343-7383. Fax: (615) 343-3916. E-mail: keith.p.choe{at}vanderbilt.edu

{triangledown} Published ahead of print on 9 March 2009.

{dagger} K.P.C. and A.J.P. are co-first authors.

Molecular and Cellular Biology, May 2009, p. 2704-2715, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01811-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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