Molecular Basis of Cell and Developmental Biology
The Unfolded Protein Response Modulates Toxicity of the Expanded Glutamine Androgen Receptor*

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Kennedy disease, a degenerative disorder caused by an expanded glutamine tract, is mediated by misfolding of the mutant androgen receptor (AR) protein, a process that may disrupt proteasome function. We hypothesized that this might lead to endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR), a complex physiologic pathway that regulates cell survival. To test this hypothesis, we used aminoterminal fragments of wild type (AR16Q) or mutant (AR112Q) AR that triggered glutamine length-dependent cell death and activated an ER stress-inducible promoter. To evaluate the role of the UPR, we examined the contributions of three proximal sensors of ER stress: activating transcription factor 6 (ATF6), inositol requiring 1 (IRE1), and PKR-like endoplasmic reticulum kinase (PERK). AR112Q toxicity was significantly increased by a dominant negative ATF6 mutant and significantly decreased by a constitutively active ATF6 mutant, indicating that ATF6 promoted cell survival. In contrast, co-transfection with three separate IRE1α dominant negative mutants failed to alter glutamine length-dependent toxicity, suggesting that this arm of the UPR did not significantly affect AR112Q induced cell death. Activation of PERK, an ER transmembrane protein that functions as the third proximal UPR sensor, promoted glutamine length-dependent toxicity. Although nuclear localization sequence- and nuclear export sequence-targeted proteins both activated the UPR, this pathway more potently influenced toxicity when proteins were targeted to the cytoplasm. Taken together, our data demonstrate that the UPR is activated in cells expressing long glutamine tracts and that this pathway modulates polyglutamine toxicity.

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This work was supported by a Beeson Career Development Award from the National Institutes of Health and American Federation for Aging Research (K08 AG024758) and by Grant P50 AG08671 from the National Institutes of Health and a grant from the Muscular Dystrophy Association (to A. P. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.