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Journal of Biochemistry Advance Access originally published online on July 29, 2008
Journal of Biochemistry 2008 144(4):477-486; doi:10.1093/jb/mvn091
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© 2008 The Japanese Biochemical Society.

Human HRD1 Promoter Carries a Functional Unfolded Protein Response Element to Which XBP1 but not ATF6 Directly Binds

Keisuke Yamamoto1,*, Natsumi Suzuki1,*, Tadashi Wada1,*, Tetsuya Okada1, Hiderou Yoshida1, Randal J. Kaufman2,3,4 and Kazutoshi Mori1,{dagger}

1Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan; 2Howard Hughes Medical Institute; 3Department of Biological Chemistry; and 4Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, USA

{dagger}To whom correspondence should be addressed. Tel: +81-75-753-4067, Fax: +81-75-753-3718, E-mail: kazu.mori{at}bio.mbox.media.kyoto-u.ac.jp

Received January 12, 2008; Accepted July 8, 2008


  Abstract

Quality control of proteins in the endoplasmic reticulum (ER) is achieved by two mechanisms, the productive folding mechanism, which is assisted by a number of ER-localized molecular chaperones and folding enzymes (collectively termed ER chaperones), and the ER-associated degradation (ERAD) mechanism, by which misfolded proteins are degraded by the ubiquitin-dependent proteasome system in the cytosol. Accumulation of unfolded proteins in the ER activates the unfolded protein response (UPR), resulting in transcriptional induction of ER chaperones and ERAD components. In mammals, three signalling pathways operate for the UPR, namely the IRE1-XBP1, PERK-ATF4 and ATF6 pathways. Analysis of mouse embryonic fibroblasts deficient in UPR signalling molecule indicates that transcriptional induction of ERAD components depends on the IRE1-XBP1 pathway. However, the molecular basis of this finding remains unclear. Here, we analysed the promoter of human HRD1, which encodes an E3 ubiquitin ligase, an important component of ERAD. We found that induction of HRD1 is mediated by two cis-acting elements, a canonical ER stress response element and a novel element we designate as UPR element II. The presence of UPR element II to which XBP1 but not ATF6 directly binds explains at least in part the dependency of HRD1 induction on the IRE1-XBP1 pathway.

Key Words: cis-element, degradation, ER, protein folding, transcription factor

Abbreviations: DIG, digoxigenin; EMSA, electrophoretic mobility shift assay; ER, endoplasmic reticulum; ERAD, ER-associated degradation; ERSE, ER stress response element; MEFs, mouse embryonic fibroblasts; UPR, unfolded protein response; UPRE, UPR element

*These three authors contributed equally to this work.


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