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Artemisinin is a sesquiterpene lactone produced by the Chinese traditional herb Artemisia annua and is used for the treatment of malaria. It is known that salicylic acid (SA) can enhance artemisinin content but the mechanism by which it does so is not known. In this study, we systematically investigated a basic leucine zipper family transcription factor, AaTGA6, involved in SA signaling to regulate artemisinin biosynthesis. We found specific in vivo and in vitro binding of the AaTGA6 protein to a 'TGACG' element in the AaERF1 promoter. Moreover, we demonstrated that AaNPR1 can interact with AaTGA6 and enhance its DNA-binding activity to its cognate promoter element 'TGACG' in the promoter of AaERF1 , thus enhancing artemisinin biosynthesis. The artemisinin contents in AaTGA6-overexpressing and RNAi transgenic plants were increased by 90–120% and decreased by 20–60%, respectively, indicating that AaTGA6 plays a positive role in artemisinin biosynthesis. Importantly, heterodimerization with AaTGA3 significantly inhibits the DNA-binding activity of AaTGA6 and plays a negative role in target gene activation. In conclusion, we demonstrate that binding of AaTGA6 to the promoter of the artemisinin-regulatory gene AaERF1 is enhanced by AaNPR1 and inhibited by AaTGA3. Based on these findings, AaTGA6 has potential value in the genetic engineering of artemisinin production. [ABSTRACT FROM AUTHOR]

Plants regulate the synthesis of specialized compounds through the actions of individual transcription factors (TFs) or sets of TFs. One such compound, artemisinin from Artemisia annua, is widely used as a pharmacological product in the first-line treatment of malaria. However, the emergence of resistance to artemisinin in Plasmodium species, as well as its low production rates, have required innovative treatments such as exploiting the synergistic effects of flavonoids with artemisinin. We overview current knowledge about flavonoid and artemisinin transcriptional regulation in A. annua , and review the dual action of TFs and structural genes that can regulate both pathways simultaneously. Understanding the concerted action of these TFs and their associated structural genes can guide the development of strategies to further improve flavonoid and artemisinin production. It is increasingly recognized that different TFs act conjointly to regulate the production of plant metabolites. However, their dual functionality in regulating distinct pathways of synthesis has not been well studied. The identification of cis- regulatory elements within the promoter regions of genes encoding different pathway enzymes enables the identification of TF families that regulate their expression. Parallel regulation of the enzyme-coding genes for distinct pathways can simplify overexpression strategies. This provides an excellent starting point to unravel how individual TFs act in a coordinated manner to simultaneously regulate different pathways of specialized metabolism. [ABSTRACT FROM AUTHOR]