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J. Biol. Chem., Vol. 282, Issue 31, 22865-22878, August 3, 2007

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Effects of the Isoform-specific Characteristics of ATF6 and ATF6 on Endoplasmic Reticulum Stress Response Gene Expression and Cell Viability^*

From the San Diego State University Heart Institute and Department of Biology, San Diego State University, San Diego, California 92182

The endoplasmic reticulum (ER)-transmembrane proteins, ATF6 and ATF6, are cleaved during the ER stress response (ERSR). The resulting N-terminal fragments (N-ATF6 and N-ATF6) have conserved DNA-binding domains and divergent transcriptional activation domains. N-ATF6 and N-ATF6 translocate to the nucleus, bind to specific regulatory elements, and influence expression of ERSR genes, such as glucose-regulated protein 78 (GRP78), that contribute to resolving the ERSR, thus, enhancing cell viability. We previously showed that N-ATF6 is a rapidly degraded, strong transcriptional activator, whereas is a slowly degraded, weak activator. In this study we explored the molecular basis and functional impact of these isoform-specific characteristics in HeLa cells. Mutants in the transcriptional activation domain or DNA-binding domain of N-ATF6 exhibited loss of function and increased expression, the latter of which suggested decreased rates of degradation. Fusing N-ATF6 to the mutant estrogen receptor generated N-ATF6-MER, which, without tamoxifen exhibited loss-of-function and high expression, but in the presence of tamoxifen N-ATF6-MER exhibited gain-of-function and low expression. N-ATF6 conferred loss-of-function and high expression to N-ATF6, suggesting that ATF6 is an endogenous inhibitor of ATF6. In vitro DNA binding experiments showed that recombinant N-ATF6 inhibited the binding of recombinant N-ATF6 to an ERSR element from the GRP78 promoter. Moreover, siRNA-mediated knock-down of endogenous ATF6 increased GRP78 promoter activity and GRP78 gene expression, as well as augmenting cell viability. Thus, the relative levels of ATF6 and -, may contribute to regulating the strength and duration of ATF6-dependent ERSR gene induction and cell viability.

Received for publication, February 8, 2007 , and in revised form, May 22, 2007.

^* This work was supported in part by National Institutes of Health Grants HL75573 and NS025037 (to C. C. G.). 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.

¹ Funded by a San Diego State University Heart Institute/Rees-Sealy Research Foundation graduate fellowship, and a graduate fellowship from the San Diego Chapter of the Achievment Rewards for College Scientists Foundation.

² To whom correspondence should be addressed: Dept. of Biology, San Diego State University, 5300 Campanile Drive, San Diego CA 92182. Tel.: 619-594-2959; Fax: 619-594-5676; E-mail: cglembotski{at}sciences.sdsu.edu.

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