Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability.

Abstract

The endoplasmic reticulum (ER)-transmembrane proteins, ATF6 alpha and ATF6 beta, are cleaved during the ER stress response (ERSR). The resulting N-terminal fragments (N-ATF6 alpha and N-ATF6 beta) have conserved DNA-binding domains and divergent transcriptional activation domains. N-ATF6 alpha and N-ATF6 beta 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 alpha is a rapidly degraded, strong transcriptional activator, whereas beta 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 alpha exhibited loss of function and increased expression, the latter of which suggested decreased rates of degradation. Fusing N-ATF6 alpha to the mutant estrogen receptor generated N-ATF6 alpha-MER, which, without tamoxifen exhibited loss-of-function and high expression, but in the presence of tamoxifen N-ATF6 alpha-MER exhibited gain-of-function and low expression. N-ATF6 beta conferred loss-of-function and high expression to N-ATF6 alpha, suggesting that ATF6 beta is an endogenous inhibitor of ATF6 alpha. In vitro DNA binding experiments showed that recombinant N-ATF6 beta inhibited the binding of recombinant N-ATF6 alpha to an ERSR element from the GRP78 promoter. Moreover, siRNA-mediated knock-down of endogenous ATF6 beta increased GRP78 promoter activity and GRP78 gene expression, as well as augmenting cell viability. Thus, the relative levels of ATF6 alpha and -beta, may contribute to regulating the strength and duration of ATF6-dependent ERSR gene induction and cell viability.

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@article{Thuerauf2007EffectsOT, title={Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability.}, author={Donna J. Thuerauf and Marie C Marcinko and Peter J. Belmont and Christopher C . Glembotski}, journal={The Journal of biological chemistry}, year={2007}, volume={282 31}, pages={22865-78} }