Abstract

Curcumin (diferuloylmethane), a major active component of turmeric (Curcuma longa), is a natural polyphenolic compound. Herein the effect of curcumin on endoplasmic reticulum (ER) stress responsive gene expression was investigated. We report that curcumin induces transcriptional corepressor small heterodimer partner-interacting leucine zipper protein (SMILE) gene expression through liver kinase B1 (LKB1)/adenosine monophosphate-activated kinase (AMPK) signaling pathway and represses ER stress-responsive gene transcription in an ER-bound transcription factor specific manner. cAMP responsive element-binding protein H (CREBH) and activating transcription factor 6 (ATF6) are both ER-bound bZIP family transcription factors that are activated upon ER stress. Of interest, we observed that both curcumin treatment and SMILE overexpression only represses CREBH-mediated transactivation of the target gene but not ATF6-mediated transactivation. Knockdown of endogenous SMILE significantly releases the inhibitory effect of curcumin on CREBH transactivation. Intrinsic repressive activity of SMILE is observed in the Gal4 fusion system, and the intrinsic repressive domain is mapped to the C terminus of SMILE spanning amino acid residues 203-269, corresponding to the basic region leucine zipper (bZIP) domain. In vivo interaction assay revealed that through its bZIP domain, SMILE interacts with CREBH and inhibits its transcriptional activity. Interestingly, we observed that SMILE does not interact with ATF6. Furthermore, competition between SMILE and the coactivator peroxisome proliferator-activated receptor α (PGC-1α) on CREBH transactivation has been demonstrated in vitro and in vivo. Finally, chromatin immunoprecipitation assays revealed that curcumin decreases the binding of PGC-1α and CREBH on target gene promoter in a SMILE-dependent manner. Overall, for the first time we suggest a novel phenomenon that the curcumin/LKB1/AMPK/SMILE/PGC1α pathway differentially regulates ER stress-mediated gene transcription.

Highlights

  • Curcumin has been reported to play an important role in endoplasmic reticulum (ER) stress

  • We report that curcumin induces transcriptional corepressor small heterodimer partner-interacting leucine zipper protein (SMILE) gene expression through liver kinase B1 (LKB1)/adenosine monophosphate-activated kinase (AMPK) signaling pathway and represses ER stress-responsive gene transcription in an ERbound transcription factor specific manner. cAMP responsive element-binding protein H (CREBH) and activating transcription factor 6 (ATF6) are both ER-bound basic region leucine zipper (bZIP) family transcription factors that are activated upon ER stress

  • Curcumin Differentially Inhibits ER Stress-regulated Gene Expression—It was previously reported that tunicamycin activates both CREBH and ATF6 protein [21, 22]

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Summary

Background

Curcumin has been reported to play an important role in ER stress. Results: Curcumin blocks the CREBH-mediated transactivation of target gene, whereas it has no such effect on ATF6-mediated transactivation. We report that curcumin induces transcriptional corepressor small heterodimer partner-interacting leucine zipper protein (SMILE) gene expression through liver kinase B1 (LKB1)/adenosine monophosphate-activated kinase (AMPK) signaling pathway and represses ER stress-responsive gene transcription in an ERbound transcription factor specific manner. Tunicamycin (Tm) is a well known ER stress inducer that has been used to activate CREBH, ATF6, and other ER stress-regulated chaperon proteins [22, 23, 26] In this current study we demonstrate that curcumin activates LKB1 and decreases the cellular ATP level that activates AMPK. Through its bZIP domain, SMILE interacts with CREBH and not with ATF6 and inhibits CREBH transcriptional activity via competition with co-activator PGC1␣, thereby highlighting a novel mechanism of differential repressive action of curcumin on ER stress-regulated genes

EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
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