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Abstract
Artemisinin is an effective antimalarial sesquiterpene lactone synthesized in Artemisia annua. Various transcription factors have been previously reported that can influence the biosynthesis of artemisinin; however, the effect of YABBY family transcription factors on artemisinin biosynthesis was unknown. In the present study, we cloned and characterized AaYABBY5: a homolog of MsYABBY5 in Mentha spicata which is involved in modulating the monoterpenes, as a positive regulator of artemisinin biosynthesis in A. annua. AaYABBY5 was found localized to the nucleus, and its expression was found to be induced by exogenous methyl jasmonic acid (MeJA) treatment. In the dual-luciferase reporter assay, it was found that AaYABBY5 significantly increased the activities of promoters of amorpha-4,11-diene synthase (ADS), cytochrome P450 monooxygenase (CYP71AV1), double-bond reductase 2 (DBR2), and aldehyde dehydrogenase 1 (ALDH1) genes. Yeast one hybrid assay showed that AaYABBY5 directly bonds to the promoters of CYP71AV1 and DBR2 genes. Quantitative real-time polymerase chain reaction (qPCR) of AaYABBY5 overexpression and AaYABBY5 antisense plants revealed a significant increase in the expression of ADS, CYP71AV1, DBR2, and ALDH1 in AaYABBY5 overexpression plants and a significant decrease in the expression of these genes in AaYABBY5 antisense A. annua, respectively. Furthermore, the results of high-performance liquid chromatography (HPLC) showed that the artemisinin and its precursor dihydroartemisinic acid were significantly increased in the AaYABBY5 overexpression plants while AaYABBY5 downregulation resulted in a significant decrease in the concentration of artemisinin. Taken together, these results explicitly represent that AaYABBY5 is a positive regulator of artemisinin biosynthesis in A. annua.
Highlights
Malaria is the most severe form of illness in human history
To find the putative Transcription factors (TFs) that belong to the YABBY family, the whole-genome database of A. annua developed by our lab (Shen et al, 2018) was screened for YABBY family domains
In order to select the TFs from the YABBY family in A. annua, which might be involved in the regulation of artemisinin, we searched for a homolog of MsYABBY5, a negative regulator of monoterpenes in M. spicata (Wang et al, 2016), based on phylogenetic analysis using protein sequences from the AaYABBY family and MsYABBY5
Summary
The ratio of this killer disease has declined during the last decade, it is still an intricate problem. There were an estimated 219 million cases and 435,000 related deaths reported in 2017 according to the World Health Organization (2018). Artemisinin, a sesquiterpene lactone, is currently the best therapeutic agent against malaria-causing strains of Plasmodium falciparum (Weathers et al, 2006). Artemisininbased combination therapies (ACTs) as recommended by the WHO are the best choice to cure acute malaria (WHO, 2018). It has saved millions of lives in African countries. Artemisinin is considered to be a potential drug for treatment of various diseases. The Chinese pharmacologist Youyou Tu is best known for her contribution to the isolation of artemisinin, and she received the 2011 Lasker Award in clinical medicine and the 2015 Nobel Prize in Physiology or Medicine
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