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Vol. 18, Issue 2, 426-440, February 2007

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SCF^Cdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response in Saccharomyces cerevisiae

Bhupinder Pal^*, Nickie C. Chan^*,, Leon Helfenbaum^*, Kaeling Tan^*, William P. Tansey, and Mary-Jane Gething^*

*Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3010, Australia; and Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724

Submitted April 13, 2006; Revised October 19, 2006; Accepted November 2, 2006
Monitoring Editor: Jeffrey Brodsky

The Saccharomyces cerevisiae basic leucine zipper transcription factor Hac1p is synthesized in response to the accumulation of unfolded polypeptides in the lumen of the endoplasmic reticulum (ER), and it is responsible for up-regulation of 5% of all yeast genes, including ER-resident chaperones and protein-folding catalysts. Hac1p is one of the most short-lived yeast proteins, having a half-life of 1.5 min. Here, we have shown that Hac1p harbors a functional PEST degron and that degradation of Hac1p by the proteasome involves the E2 ubiquitin-conjugating enzyme Ubc3/Cdc34p and the SCF^Cdc4 E3 complex. Consistent with the known nuclear localization of Cdc4p, rapid degradation of Hac1p requires the presence of a functional nuclear localization sequence, which we demonstrated to involve basic residues in the sequence ₂₉RKRAKTK₃₅. Two-hybrid analysis demonstrated that the PEST-dependent interaction of Hac1p with Cdc4p requires Ser146 and Ser149. Turnover of Hac1p may be dependent on transcription because it is inhibited in cell mutants lacking Srb10 kinase, a component of the SRB/mediator module of the RNA polymerase II holoenzyme. Stabilization of Hac1p by point mutation or deletion, or as the consequence of defects in components of the degradation pathway, results in increased unfolded protein response element-dependent transcription and improved cell viability under ER stress conditions.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Mary-Jane Gething (m.gething{at}unimelb.edu.au)

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