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Molecular and Cellular Biology, November 2006, p. 7999-8010, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.01046-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Luman/CREB3 Induces Transcription of the Endoplasmic Reticulum (ER) Stress Response Protein Herp through an ER Stress Response Element{triangledown}

Genqing Liang,1 Timothy E. Audas,1 Yu Li,1 Gregory P. Cockram,1 J. Doug Dean,1,{dagger} Amanda C. Martyn,1 Koichi Kokame,2 and Rui Lu1*

Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada,1 National Cardiovascular Centre Research Institute, Suita, Osaka, Japan2

Received 9 June 2006/ Returned for modification 31 July 2006/ Accepted 16 August 2006

Luman/CREB3 (also called LZIP) is an endoplasmic reticulum (ER) membrane-bound transcription factor which is believed to undergo regulated intramembrane proteolysis in response to cellular cues. We previously found that Luman activates transcription from the unfolded protein response element. Here we report the identification of Herp, a gene involved in ER stress-associated protein degradation (ERAD), as a direct target of Luman. We found that Luman was transcriptionally induced and proteolytically activated by the ER stress inducer thaspsigargin. Overexpression of Luman activated transcription of cellular Herp via ER stress response element II (ERSE-II; ATTGG-N-CCACG) in the promoter region. Mutagenesis studies and chromatin immunoprecipitation assays showed that Luman physically associates with the Herp promoter, specifically the second half-site (CCACG) of ERSE-II. Luman was also necessary for the full activation of Herp during the ER stress response, since Luman small interfering RNA knockdown or functional repression by a dominant negative mutant attenuated Herp gene expression. Like Herp, overexpression of Luman protected cells against ER stress-induced apoptosis. With Luman structurally similar to ATF6 but resembling XBP1 in DNA-binding specificities, we propose that Luman is a novel factor that plays a role in ERAD and a converging point for various signaling pathways channeling through the ER.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada N1G 2W1. Phone: (519) 824-4120, ext. 56247. Fax: (519) 767-1656. E-mail: rlu{at}uoguelph.ca.

{triangledown} Published ahead of print on 28 August 2006.

{dagger} Present address: The University Health Network Microarray Center, Toronto, Ontario, Canada M5G 1L7.

Molecular and Cellular Biology, November 2006, p. 7999-8010, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.01046-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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