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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 3  |  Page : 307-325

Phytohormones jasmonic acid, salicylic acid, gibberellins, and abscisic acid are key mediators of plant secondary metabolites


1 Research and Development Center of Chinese Medicine Resources and Biotechnology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203; Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
2 Research and Development Center of Chinese Medicine Resources and Biotechnology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
3 Department of Pharmaceutical Botany, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

Date of Submission13-Aug-2020
Date of Acceptance24-Nov-2020
Date of Web Publication09-Apr-2021

Correspondence Address:
Prof. Lei Zhang
Department of Pharmaceutical Botany, School of Pharmacy, Second Military Medical University, Shanghai 200433
China
Prof. Wan-Sheng Chen
Research and Development Center of Chinese Medicine Resources and Biotechnology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_20_21

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  Abstract 


Until recently, many studies on the role of phytohormones in plant secondary metabolism focused on jasmonic acid (JA), salicylic acid (SA), gibberellins (GA), and abscisic acid (ABA). It is now clear that phytohormone-induced regulation of signaling occurs via regulation of the biosynthetic pathway genes at the transcriptional level or through posttranslational regulation, or an increase in secondary metabolite deposition (e.g., trichomes). Here, we summarize recent advances, updating the current reports on the molecular machinery of phytohormones JA, SA, GA, and ABA involved in plant secondary metabolites. This review emphasizes the differences and similarities among the four phytohormones in regulating various secondary metabolic biosynthetic pathways and also provides suggestions for further research.

Keywords: Abscisic acid, gibberellins, jasmonic acid, salicylic acid, secondary metabolism


How to cite this article:
Lv ZY, Sun WJ, Jiang R, Chen JF, Ying X, Zhang L, Chen WS. Phytohormones jasmonic acid, salicylic acid, gibberellins, and abscisic acid are key mediators of plant secondary metabolites. World J Tradit Chin Med 2021;7:307-25

How to cite this URL:
Lv ZY, Sun WJ, Jiang R, Chen JF, Ying X, Zhang L, Chen WS. Phytohormones jasmonic acid, salicylic acid, gibberellins, and abscisic acid are key mediators of plant secondary metabolites. World J Tradit Chin Med [serial online] 2021 [cited 2022 Jun 29];7:307-25. Available from: https://www.wjtcm.net/text.asp?2021/7/3/307/323495




  Introduction Top


There are many types of secondary metabolites in plants.[1] In general, natural products are divided into four major categories based on biosynthetic origin: terpenoids, polyketides, phenylpropanoids, and alkaloids. For nearly 50 years, secondary metabolites have been well known for protecting plants against herbivores, pathogens, competitors, microbial attacks, or UV irradiation.[2] For example, the sesquiterpene β-caryophyllene is emitted by maize in response to attack by Spodoptera littoralis.[3] Another sesquiterpene, β-farnesene, i.e., the aphid alarm pheromone, leads to dispersion in response to attack by an aphid.[4] Anthocyanin pigments act as attractors of flower pollinators.[5] Cyanogenic glycosides and glucosinolates play central roles in plant resistance to insects and pathogens.[6] The proanthocyanidins in the seed coat of Artemisia thaliana are widely believed to act as regulators of seed longevity and dormancy.[7]

Besides, secondary metabolites play an important role in human health. The tropane alkaloids are used to control motion sickness and Parkinson's disease and are also used as mydriatics. The phenolic acid compound salvianolic acid B has various bioactivities, including anti-inflammatory, antioxidant, and anticancer properties, and is also used to treat cardiovascular and cerebrovascular diseases.[8] The sesquiterpene artemisinin has a critical role in treating malaria[9] [Figure 1].
Figure 1: Typical metabolites in plants are induced by phytohormone. The sesquiterpene compound artemisinin, dihydroartemisinic acid, and artemisinic acid are the important drugs for the treatment of malaria in Artemisia annua. The monoterpenoid indole alkaloid-type metabolites vinblastine, vindoline, and catharanthine are the anticancer drugs from Catharanthus roseus. Phenolic acids and tanshinone are natural products in Salvia miltiorrhiza and are effective ingredients for treating coronary heart disease. Flavonoids in Arabidopsis are important natural compounds for plants to resist pests and diseases

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Plant hormones play an important role in modulating plant growth, development, reproduction, secondary metabolism, and defense. Many plant hormones regulate secondary metabolisms, such as jasmonic acid (JA), salicylic acid (SA), and abscisic acid (ABA). Plant hormones serve as conserved elicitors of plant secondary metabolism and trigger transcriptional reprogramming, leading to a redirection of the metabolic flux mainly toward secondary metabolic pathways. For example, JA signaling controls terpenoid indole alkaloid biosynthesis, indole glucosinolates, anthocyanin biosynthesis, and phenylpropanoid biosynthesis.[10] SA-mediated induction of anthocyanins, furanocoumarins, alkaloids, glucosinolates, and phenolics has been reported in plants.[11] GA and ABA influence the synthesis of monoterpenes and sesquiterpenes and are known to be essential for dealing with biotic and abiotic stresses[12] [Figure 1].


  The Sites of Biosynthesis and Storage of Plant Secondary Metabolites Top


Plants protect themselves against insects, herbivores, and microorganisms by physical methods, such as cuticles of roots and stems, thorns, trichomes, and stinging hairs, or chemical methods such as the production of alkaloids, terpenoids, flavonoids, and phenylpropanoids. However, secondary metabolites are toxic to plants, so plants must synthesize and store these compounds without poisoning themselves.[13] These toxins can be synthesized with an inactive precursor that separates activating enzymes that accumulate in special tissues, such as trichomes, roots, and vacuoles. Flavonoid compounds, such as isoflavones, anthocyanins, and proanthocyanidins, are found in the leaves, flowers, and fruits of many plant species and are stored in the vacuole.[14] Most terpenoid indole alkaloids (such as catharanthine, ajmalicine, and strictosidine) in Catharanthus roseus accumulate in the vacuoles of idioblast cells and laticifer cells.[15] Nicotine is an important alkaloid specially synthesized in roots and is distributed throughout the plant via the xylem.[16] Ginkgolic acids and cardanols are found specifically in the secretory cavities in the leaves of Ginkgo biloba.[17] Terpenoids, consisting of monoterpene, sesquiterpene, and diterpene, play an essential role in both plant and animal life. Most terpenoids are stored in trichomes. Matrix-assisted laser desorption ionization mass spectrometry showed that diterpenes in Nepeta are stored in the trichomes on the surface of leaves and fruit.[18] Artemisinin, which is used as an antimalarial drug, is synthesized and stored in the glandular trichomes of Artemisia annua.[19]

Trichomes, which are unicellular or multicellular appendages that originate from epidermal cells, are found on the surfaces of stems, buds, and leaves of plants. According to their morphology, trichomes can be divided into two types: glandular or nonglandular trichomes (T-shaped). Arabidopsis trichomes are single celled and nonglandular.[20],[21] Glandular secretory trichomes store or release a wide variety of different chemical substances. In A. annua, the glandular secretory trichome consists of 10 cells, three pairs of secretory cells, two stalks, and two basal cells [Figure 2]. The sesquiterpenoids and monoterpenoids are secreted into and accumulated in the subcuticular space by some transporters.[22],[23]
Figure 2: Glandular trichome of Artemisia annua. (a) Autofluorescence of glandular trichome in the leaves with the FITC filter (λex = 480 nm; λem = 535 nm). (b) Scanning electron microscope analysis of the surface of Artemisia annua leaves. (c) Autofluorescence of glandular trichome in the bud. (d) The morphologies of the glandular trichome on the leaf

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  Plant Hormone Signaling in Plants Top


Jasmonic acid

Jasmonic acid biosynthesis

JA is a derivative of lipids, acting as a vital signaling compound in plant development, stress responses, and secondary metabolism modulation. JA is the product of the oxidative metabolism of polyunsaturated fatty acids (PUFAs) [Figure 3]. Under the activation of phospholipase A1, α-linolenic acid can be released from chloroplast membranes. The enzyme lipoxygenase can oxidize linolenic acid to form 13(S)-hydroxy linolenic acid (13-HPOT). 12-oxo-phytodienoic acid (OPDA) is formed from 13-HPOT in two steps via allene oxide synthase (AOS) and allene oxide cyclase.[24],[25] OPDA is then converted to JA by OPDA reductase 3 (OPR3) and β-oxidation. MeJA is formed from JA via carboxyl methyltransferase (JMT).[26] However, in the absence of OPR3, OPDA uses 4,5-didehydrojasmonate for jasmonate synthesis.[27] JA is not the bioactive compound of JA but JA-isoleucine (JA-Ile), and JA-Ile regulates hormonal signal transduction. The enzyme jasmonate amino acid synthetase 1 (JAR1) catalyzes the conjunction of JA and Ile to generate JA-Ile[28] [Figure 3]. Interestingly, JA can be synthesized in the process of defense against herbivory. The JAV1–JAZ8–WRKY51 complex is induced by insect attack. The wound-induced phosphorylation of JAV1 plays an important role in activating JA biosynthesis.[29]
Figure 3: Jasmonic acid biosynthesis pathway. The lipoxygenase can catalyze the oxidation reaction of α-linolenic acid to generate 13(s)-hydroxy linolenic acid. The substrate 13(s)-hydroxy linolenic acid conversion into 12-oxo-phytodienoic acid by the action of allene oxide synthase and allene oxide cyclase. 12-oxo-phytodienoic acid is reduced by 12-oxo-phytodienoic acid reductase and three cycles of β-oxidation generation of jasmonic acid. Jasmonic acid can be converted into many derivatives, e.g., MeJA, 12-OH-JA, JA-IIe, JA-IIe-Me. Jasmonic acid can be converted to jasmonic acid-IIe and MeJA by jasmonate resistant 1 and jasmonic acid carboxyl methyltransferase, respectively. MeJA esterase that converts MeJA into jasmonic acid

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However, there are many questions to be solved. OPDA is produced in the chloroplast and has to be transported into peroxisomes, while no transporter has been identified so far. However, an ATP-binding cassette (ABC) transporter that can import JA precursors across the peroxisome membrane has been detected in an indirect assay.[30]

Jasmonic acid signaling

Jasmonate signaling can be activated by many elicitors, such as cold and freezing stress, insect defense, wounding, and UV irradiation. The jasmonate signaling-mutant coronatine-insensitive 1 (COI1) was first identified as an F-box component of an SKIP/CULLIN/F-box complex (SCF).[31] The SCF complex is a type of multiprotein E3 ubiquitin ligase that plays a vital role in catalyzing Ub-mediated proteolysis.[32] A new protein family, jasmonate ZIM domain (JAZ), was identified in 2007.[33] JAZ proteins play a negative role in the modulation of JA-induced gene expression. In the presence of JA, the F-box component COI1 specifically distinguishes JAZ proteins and targets them for degradation.[34],[35],[36] Therefore, JAZ plays a linking role between JA-Ile and MYC transcription factors (TFs).[37],[38] JAZ proteins directly interact with COI1 in a JA-dependent manner, which was identified by yeast two-hybrid and pull-down analyses.[39],[40],[41] However, small ubiquitin-like modifier prevents JAZ proteins from binding to COI1.[42] The mediator subunit MED25 directly interacts with JAZ proteins and COI1, facilitating JAZ protein degradation by JA-Ile and enhancement of MYC2 gene function by MED25–MYC2 interaction.[43]

Jasmonate-insensitive 1 (JIN1) and JAR1 are considered JA signaling loci based on the analysis jar1 and jin1 mutants in Arabidopsis. JAR1 is a JA amino acid synthetase involved in the conjugation between JA and Ile.[44] Plastid lipase 2 (PLIP2) and PLIP3 can be induced by ABA and can enhance the synthesis of precursors (PUFA; OPDA) of JA-Ile.[45] MYC2 is a basic helix–loop–helix (bHLH) TF involved in the modulation of gene expression [Figure 4].[46] MYC2 levels can be positively regulated by deubiquitinating enzymes ubiquitin-specific proteases 12 (UBP12) and UBP13 to increase JA response.[47]
Figure 4: Jasmonic acid signaling is involved in secondary metabolite biosynthesis in Artemisia annua, Salvia miltiorrhiza, tobacco, and Arabidopsis. Hormone signaling involves the regulation of secondary metabolites via changes in the mRNA levels of transcription factors. jasmonate ZIM domain proteins are negative regulators in the jasmonic acid signaling pathway that inhibit the activity of transcription factors. When jasmonic acid concentrations increase, jasmonic acid receptor coronatine-insensitive 1 binds to jasmonate ZIM domain and drives jasmonate ZIM domain degradation, leading to the activation of jasmonic acid signal transduction. (a) Artemisinin biosynthesis in Artemisia annua. (b) Tanshinones and phenolic acid biosynthesis in Salvia miltiorrhiza. (c) Nicotine biosynthesis in Nicotiana benthamiana. (d) Sesquiterpene biosynthesis in Arabidopsis. COI1: Coronatine-insensitive 1, JAZ: Jasmonate ZIM domain, Ja-lle: Jasmonyl-isoleucine

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However, the function of MYC2–MED25 transcriptional activation complex can be impaired by JA-inducible bHLH proteins: MYC2-targeted bHLH1 (MTB1), MTB2, and MTB3 to form a feedback loop. The feedback loop mainly focuses on the expression of JA-mediated response genes.[48] The upstream signal transduction pathways of MTB1, MTB2, and MTB3 are still unknown, and further study is needed. Whether and how MYC2 may be regulated by posttranslational modification remains to be studied.

Abscisic acid

Abscisic acid biosynthesis

ABA plays a central role in the plant abiotic and biotic stress responses. Its synthesis starts with beta-carotene [Figure 5]. β-carotene hydroxylase (Chyb) catalyzed hydroxylation of β-carotene to yield zeaxanthin. β-carotene-derived zeaxanthin can be converted into violaxanthin via zeaxanthin epoxidase. The compound 9-cis-neoxanthin is formed from violaxanthin in two steps via neoxanthin synthase and isomerase, respectively. Isomerase may convert violaxanthin into 9-cis-violaxanthin as well. Xanthoxin is formed from catalyzing 9-cis-neoxanthin and 9-cis-violaxanthin via 9-cis-epoxycarotenoid dioxygenase, which is a rate-limiting enzyme in the ABA biosynthesis.[49] Then, xanthoxin can be converted into ABA via short-chain alcohol dehydrogenase and abscisic aldehyde oxidase[50] [Figure 5]. ABA accumulation is usually involved in transporter AtMRP5, PDR12/ABCG40, AtABCG22, and AtABCG25.[51],[52],[53]
Figure 5: Abscisic acid biosynthesis pathway. Enzymes are shown in orange. PED: Phytoene desaturase, ZEP: Zeaxanthin epoxidase, VDE: Violaxanthin de-epoxidase, NSY: Neoxanthin synthase, NCED: 9-Cis-epoxycarotenoid dioxygenases, ABA2: Alcohol dehydrogenase, AAO3: Abscisic aldehyde oxidase, MoCo: Molydenum cofactor[50]

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The content of neoxanthin in plants is much higher than that of violaxanthin, and it is the direct precursor of neoxanthin. ABA4 protein plays a direct role in neoxanthin synthesis, indicating that ABA is derived from neoxanthin.[54] Yet, another reporter suggested that Cuscuta reflexa can synthesize ABA even though it lacks neoxanthin.[55] However, a mutant of neoxanthin-deficient 1 (nxd1) in tomato showed fitness of plant when it lacks neoxanthin and does not display an ABA deficiency phenotype. At the same time, AtNXD1 did not change the carotenoid composition in Escherichia coli cells. ABA4 protein synthesized neoxanthin, while Aba4 gene mutant did not alter the neoxanthin composition in E. coli cells as well.[56] These results suggest that violaxanthin and neoxanthin are the precursors for ABA production in vivo, but which one is the direct precursor in vivo is still unknown.

Abscisic acid signaling

The ABA-dependent signaling pathway and crosstalk with ABA-independent signaling occur in response to osmotic stress. The discovery of the protein phosphatase 2C-pyrabactin resistance/PYR1-like/regulatory components of the ABA receptor (PP2C-PYR/PYL/RCAR) protein family showed that ABA signaling modules and the PYR/PYL/RCAR complexes are ABA receptors.[50] ABA receptor PYR/PYLs can be degraded by EL1-like protein and can suppress ABA responses,[57] while RCAR can be phosphorylated by cytosolic ABA receptor kinase 1 and can activate ABA signaling.[58] ABA enhances the degradation of PP2CA via RGLG1–PP2CA interaction. However, mutations in the PP2C amino acid sequence may display negative regulation of ABA signal transduction. PP2C of Striga is not regulated by ASA receptors, and this feature is attributable to differences in specific amino acid residues in its amino acid sequence.[59]

The subclass III SNF1-related kinase 2s (SnRK2s, SRK2D/SnRK2.2, SRK2E/SnRK2.6/OST1, and SRK2I/SnRK2.3) is located downstream of PP2C-PYR/PYL/RCAR complexes and modulates protein activities by modulating phosphorylating substrates, such as flowering bHLH3/ABA-responsive kinase substrate 1, SNS1, and ABA-responsive element ABRE-binding protein/ABRE-binding factors (AREB/ABFs) in ABA signaling [Figure 6].[50],[60],[61],[62] The four AREB/ABF TFs – AREB1, AREB2, ABF3, and ABF1 – play a key role in ABA-dependent gene expression.[63] In addition, AREB1, AREB2, and ABF3 have overlapping functions involved in drought stress tolerance and need ABA for full activation.[64] ABA signaling is also reported to be increased by MYB96, which interacts with DHA15 (a histone modifier) to inhibit negative regulators of ABA signaling.[65] Analyses of the PYL6 interaction with MYC2 have provided new insights into crosstalk between ABA and JA.[66] Interestingly, ABA increases JA signaling by the degradation of JAZ proteins via the interaction between ABA-insensitive 5 and JAZ protein.[66]
Figure 6: Abscisic acid signaling is involved in secondary metabolite biosynthesis in Artemisia annua and Malus hupehensis. The pyrabactin resistance/PYR1-like/regulatory components of the abscisic acid receptor-abscisic acid-PP2C complex enhances ABA signal transduction by reducing the phosphatase activity of protein phosphatase 2C. SNF1-related kinase 2s activate ABA signal transduction by phosphorylating transcription factors. (a and b) Artemisinin and anthocyanin biosynthesis in Artemisia annua and Malus hupehensis, respectively. PYR/PYL/RCAR: Pyrabactin resistance 1/PYR1-like/regulatory components of ABA receptor; PP2C: Protein phosphatase 2C; SnRK2s: SNF1-related kinase 2s

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Gibberellins

Gibberellins biosynthesis

GAs are diterpenoid carboxylic acids that are widely found in higher plants and function as central growth regulators that are related to organ expansion and developmental changes. Geranylgeranyl diphosphate (GGPP), the precursor of GAs, is derived from the mevalonic acid pathway and originates from pyruvate and glyceraldehyde 3-phosphate in plastids. Ent-kaurene is synthesized from GGPP via ent-copalyl diphosphate synthase and ent-kaurene synthase in higher plants.[67],[68],[69] The reaction of ent-kaurene to bioactive forms is catalyzed by cytochrome P450 monooxygenases and 2-oxoglutarate-dependent dioxygenases. GA12 is believed to be the common precursor for GAs. The conversion of GA12 to GAs requires ent-kaurene oxidase and ent-kaurenoic acid oxidase. GA2oxA9 may be involved in converting the intermediate GA12 to the inactive product GA110 [Figure 7]. The mutation of GA2oxA9 may alter the responses to GA and decrease.[70] GA is a mobile hormone that can be transported from place of synthesis to place of action. The movement of GA is important for plant growth and development. NPF3 can transport GA across cell membranes in vitro.[71]
Figure 7: Gibberellins biosynthesis pathway. Enzymes are shown in orange. Dashed arrows indicate unidentified enzymatic steps in Arabidopsis. GGPP: Geranylgeranyl diphosphate, CPS: Ent-copalyl diphosphate synthase, KS: Ent-kaurenoic acid synthase, KO: Ent-kaurene oxidase, KAO: Ent-kaurenoic acid oxidase

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The sugar transporters AtSWEET13 and AtSWEET14 exhibit cellular GA uptake in vitro assay and double-mutant sweet13sweet14 of Arabidopsis change long-distant transport of exogenous GA.[72] However, all the identified GA transporters are influx transporters and GA efflux transporters have not yet been discovered. The reasons may be that GA efflux carriers play an redundant role and are difficult to test and verify them.[73]

Gibberellins signaling

GA-insensitive dwarf 1 (GID1) is believed to be the GA receptor that directly binds bioactive GAs. The GA–GID1 complex plays a positive role in degrading the growth repressors, the DELLA proteins.[74],[75],[76] DELLAs belong to the GRAS subfamily. GA insensitive (GAI), repressor of ga1-3 (RGA), and scarecrow are members of this subfamily. GA–GID1–DELLA interacts with endogenous signals and environmental cues to modulate growth and development, such as stem elongation, juvenile to adult transition, vegetative to reproductive transition, and seed germination.[77],[78],[79],[80] However, amino acid changes are crucial for GID1 activity in plant growth and development.[81] One single nucleotide mutation in GID1 (GID1cS191F) exhibits altered responses to GA and cannot interact with DELLA proteins, leading to a GAI phenotype.[82] In addition, DELLA proteins directly integrate major hormone signaling pathways by interacting with TFs[83],[84] [Figure 8].
Figure 8: Gibberellins signaling is involved in (a) anthocyanin and (b) terpene biosynthesis in Arabidopsis. DELLAs inhibit gibberellins signaling by interacting with and repressing the activity of transcription factors. The gibberellins receptor GA receptor gibberellin-insensitive 1 binds to gibberellins and activates the interaction of DELLA with the F box protein. When recruited to the F box protein, DELLA proteins are degraded through the 26S proteasome pathway. Thus, gibberellin signaling is activated. GID1, GA receptor gibberellin-insensitive 1

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Salicylic acid

Salicylic acid biosynthesis

SA is an important plant hormone in disease resistance signaling, secondary metabolite regulation, and flowering. SA is derived from two enzymatic pathways and needs the substrate chorismate, which acts as a primary metabolite and comes from the shikimate–phenylpropanoid pathway [Figure 9].[85],[86] The reaction of chorismate to SA is catalyzed by two enzymes, isochorismate synthase (ICS) and isochorismate pyruvate-lyase (IPL), in bacteria.[87] In plants, isochorismate is derived from chorismate and this reaction is also catalyzed by ICS. However, no plant IPL has been identified; therefore, it is unclear how plants biosynthesize SA from isochorismate [Figure 9]. Recently, two research groups indicated that the cytosolic amidotransferase avrPphB susceptible3 (PBS3) is involved in producing SA from isochorismate. Enhanced disease susceptibility5 (EDS5) is a transmembrane transporter that localizes in the chloroplast envelope and transports isochorismate into the cytosol. PBS3 and EDS5 play an important role in SA accumulation by completing SA biosynthesis from isochorismate.[85],[86]
Figure 9: Salicylic acid biosynthesis pathway. Enzymes are shown in orange-red. Unidentified enzymes are marked with a question tag. CM: Chorismate mutase, ICS: Isochorismate synthase, IPL: Isochorismate pyruvate-lyase, BA2H: Benzoic acid 2-hydroxylase, BZL: Benzoyl-CoA ligase, AAO: Arabidopsis aldehyde oxidase, 4CL: Hydroxycinnamate coenzyme A ligase, PAL: Phenylalanine annonia-lyase

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Transfactors WRKY28, TCP8/9, and NTL9 play a positive role in SA biosynthesis by promoting ICS expression levels, while ethylene insensitive3 and NACs (ANAC019, ANAC055, and ANAC072) play a negative role in SA biosynthesis by downregulating ICS expression levels.[88] Systemic acquired resistance deficient 1 biosynthesizes SA by activating the expression of ICS.[89] Cyclin-dependent kinase 8 and mediator kinase module member 12 serve as positive regulators of SA biosynthesis by increasing the expression of ICS1 to modulate steady-state SA levels.[90] In the cinnamic acid route, phenylalanine can be converted into SA via a series of enzymatic reactions, including phenylalanine ammonia-lyase (PAL). However, EDS5 is located on the plastid and PBS3 in the cytosol. It is not clear why ICS1, EDS5, and PBS are located in different spaces.

Salicylic acid signaling

SA is an important signaling molecule involved in plant defense. Nonexpresser of PR1 (NPR1) is involved in the regulation of approximately 95% of SA-dependent gene expression. NPR1 is a vital part of one of the SA-mediated defense signaling pathways. As a central transcriptional regulator, NPR1 is responsible for controlling most SA-dependent genes. A study indicated that NPR1 directly binds SA and may act as the receptor for SA.[91] However, another study has suggested that NPR3 and NPR4 are receptors for SA.[92] Moreover, a recent study indicated that both NPR1 and NPR3/NPR4 are SA receptors, and they exert opposite effects in the modulation of SA-induced gene expression.[93] The crystal structure changes in SA perception by NPR proteins are very important.[94] NPR3 and NPR4 can modulate JA transcriptional repressor JAZ and activate JA signaling.[95] NPR1 acts as a cofactor in association with TF modulation gene expression. NPR1 interacts with the TGA TF via ankyrin repeats to increase the DNA binding activity of the TGAs. TGAs are a subfamily of basic domain leucine zipper (bZIP) TFs and modulate gene expression by specific binding of the DNA sequence “TGACG” of the target genes [Figure 10].[96],[97],[98],[99]
Figure 10: Salicylic acid signaling is involved in secondary metabolite biosynthesis in rice and Artemisia annua. Nonexpressor of PR1/nonexpressor of PR3/nonexpressor of PR4 can bind salicylic acid and serve as salicylic acid receptors. At low levels of salicylic acid, nonexpressor of PR4-salicylic acid interacts with nonexpressor of PR1 and targets nonexpressor of PR1 for degradation. When salicylic acid levels increase, SA binds to nonexpressor of PR1 and enhances its affinity for nonexpressor of PR1-salicylic acid, thus permitting nonexpressor of PR1 to interact with TGA proteins and modulate transcription. At high levels of salicylic acid, nonexpressor of PR3-salicylic acid interacts with nonexpressor of PR1 and promotes nonexpressor of PR1 ubiquitination. (a and b) Momilactones and artemisinin biosynthesis in rice and Artemisia annua, respectively. NPR1: Nonexpressor of PR1; TGA, TGA-element binding protein

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In the SA biosynthesis process, the detailed steps from isochorismate to SA are not clear. The detailed molecular mechanism of SA acting on the receptor is not yet clear. NPR1 is so important receptor in the SA signaling pathway, while it is still unclear if some proteins regulate the expression of the NPR1 gene. The amplification cascade of the SA signal is currently unclear. Further analysis of NPR1 and the amplification cascade of the SA signal may reveal a detailed regulatory network and facilitate a better understanding of the regulation of secondary metabolite content in plants. NPR3/NPR4 are the receptors of SA and display important roles in plant immunity;[93],[100] however, whether they are involved in growth and development is unknown.


  Crosstalk of Phytohormones Signaling Pathway Top


Crosstalk between jasmonic acid and abscisic acid

JA is the conserved elicitor of plant secondary metabolites.[10] It activates the secondary metabolism biosynthetic pathway gene expression and reprograms the entire metabolic pathways. However, JA does not act independently but plays a role in complex networks with crosstalk to other phytohormones. Previously, studies have indicated that JA signaling could interact with ABA signaling through MYC2, thereby activating rd22 expression. Furthermore, ABA and JA coregulate the biosynthesis of secondary metabolites, such as terpenes in A. annua,[101],[102],[103] indole alkaloids in C. roseus, and flavone compounds in Arabidopsis.[104] There are synergistic or antagonistic interactions between ABA and JA. e.g., ABA increases artemisinin content by enhancing the expression of amorpha-4,11-diene synthase (ADS) and CYP71AV1;[101] at the same time, JA increases artemisinin content by enhancing expression of CYP71AV1 and artemisinic aldehyde λ11(13) reductase (DBR2).[105] CYP71AV1 is the target gene of ABA and JA signaling, suggesting that ABA interacts with JA through CYP71AV1 in artemisinin biosynthesis. These observations indicated that the crosstalk between phytohormones signaling pathway modulation of secondary metabolites may be achieved by regulating gene expression of the secondary metabolites pathway. However, the synergistic or antagonistic interactions between JA and ABA in artemisinin biosynthesis need further studying.

Crosstalk between jasmonic acid and salicylic acid

The crosstalk between JA and SA influences plant growth and development, plant immunity, and the accumulation of secondary metabolites. There is antagonism between SA and JA in Arabidopsis.[106] In Thevetia peruviana, crosstalk stimulation of flavonoid content (FC), phenolic compound content (PCC), and antioxidant activity was also observed with methyl jasmonate (MJ) and SA. Highest FC, PCC, and AA were induced by following treatments: 3 μM MJ > 3 μM MJ + 300 μM SA > 300 μM SA > control. The treatment of 3 μM MJ + 300 μM SA did not produce the highest secondary metabolites in T. peruviana,[107] indicating that there are antagonistic interactions between MJ and SA. SA enhances PAL transcripts and increases phenolic acid content in Salvia miltiorrhiza,[108] while MJ improves rosmarinic acid and lithospermic acid B content by increasing PAL, cinnamic acid 4-hydroxylase, hydroxycinnamate coenzyme A ligase, 4-hydroxyphenylpyruvate dioxygenase, and hydroxyphenylpyruvate dioxygenase expression.[109] The shared target of SA and MJ is PAL, suggesting that a complex crosstalk exists between SA and MJ. The evidence indicates that interactions between different inducers are complicated in the stimulation of secondary metabolites in plants. The inhibition of JA signal by SA in secondary metabolic biosynthesis is mediated by NPR1, which is a receptor for SA and plays an important role in inhibiting JA signal. In rice, OsNPR1 may repress gene expression in the JA signaling pathway, and when mutant NPR1, the expression of JA-responsive genes is normal.[110] The SA-induced gene ANAC032 can suppress the JA signaling pathway by directly inhibiting the activity of MYC2,[111] and MYC2 can regulate secondary metabolites, such as terpenes and anthocyanins. SA strongly represses JA signaling downstream of the SCF–COI1–JAZ complex by reducing the accumulation of Apetala2/ethylene responsive element binding protein (AP2/ERF) TF,[112] which plays an important role in secondary metabolites production.[10] In addition, glutaredoxin GRX480 is induced by SA and inhibits the JA-dependent defensin gene mRNA expression,[113] indicating that SA may inhibit JA signaling in plant immunity. However, JA and SA also have synergistic effects in plant immunity. SA receptors NPR3 and NPR4 may degrade the JAZs protein to enhance JA signaling and therefore increase plant immunity.[95]


  Phytohormones Increase the Deposition Site Number of Secondary Metabolites Top


Glandular trichomes not only produce secondary metabolites but are also the sites of storage. There are many secondary metabolites in trichomes, including pesticides, pharmaceuticals, and flavor and fragrance compounds. Phytohormones play an important role in promoting secondary metabolite biosynthesis. For example, under JA treatment, the contents of artemisinin, artemisinic acid, dihydroartemisinic acid, and arteannuin B are increased in A. annua.[114] In addition, phytohormones increase secondary metabolites by increasing the number of trichomes. Trichome number is directly proportional to secondary metabolites.[19],[114],[115] In tobacco, the diterpene content increased as the number of trichomes increased.[116] Secondary metabolite levels increased as trichome density increased.[19],[114] Increased trichome density may decrease secondary metabolite feedback inhibition;[117] therefore, artemisinin content is increased. In addition to modulating trichome density, phytohormones can also affect trichome size.[118] GA, JA, and SA increased the size of glandular trichomes.[114],[119]

Jasmonic acid increases trichome number

Plant endogenous JA is induced by wounded signaling and enhances trichome density.[120] Wounded signaling increases endogenous JA biosynthesis to form the bioactive form, JA-Ile.[121],[122] The AOS gene encodes a key enzyme for JA biosynthesis.[123] The aos mutants did not enhance trichome numbers when treatment with mechanical wounding.[120] Overexpression of AOS increases the number of trichomes, enhances tolerance to insect attack,[124] and upregulates the content of secondary metabolites.[125] JA treatment of unwounded plants mimics artificial damage caused significant increase in trichome production, indicating that JA is the key regulator of trichome development.[126]

JAZ plays a negative role that suppresses gene activation. Endogenous JA is increased by wounding and triggers the degradation of JAZ protein by ubiquitin/26S-proteasome. JAZ9 interacts with ERF109 and inhibits the activity of ERF109. However, under the treatment of JA, ERF109 was released from JAZ9 and activates the expression of anthranilate synthase 1, which enhances auxin content and increases the trichome number [Figure 11]a.[127],[128] In A. annua, AaHD1, an HDzip TF, acts in glandular trichome development by interacting with JAZ8. JA induces degradation of JAZ8 and releases AaHD1 from AaHD1–JAZ8 complex and increases the trichome number [Figure 11]b.[19]
Figure 11: Phytohormones regulate trichome development in Arabidopsis and A. annua. (a) Abscisic acid enhances MYB96 transcripts and promotes wax biosynthesis, leading to trichome development in Arabidopsis. However, abscisic acid increases MYB41, which is a negative regulator for cutin biosynthesis. Trichomes derive from epidermal cells of the leaves or stems. The initial trichome modulated by jasmonic acid, gibberellins, auxin/IAA, or abscisic acid. Jasmonic acid-induced degradation of jasmonate ZIM domain releases ERF109, which is a positive regulator for anthranilate synthase 1 (Zhang et al., 2019). ERF109 was released from jasmonate ZIM domain 9 and activates the expression of ASA1, which enhances auxin content and increases the trichome number. At the same time, GL1 and GL3 are induced by jasmonic acid and enhances the transcripts of GL2, and then increase the trichome density. GL1 is downstream of gibberellins. (b) In the trichome development of Artemisia annua, jasmonate ZIM domain protein was degraded by ubiquitin/26S-proteasome, leading to AaHD1 released from jasmonate ZIM domain. AaHD8 interacts with AaMIXTA1, which is an important regulator for cuticle biosynthesis and trichome initiation by directly binding to the promoter of AaHD1. AaMYB1 can promote gibberellins synthesis and enhance trichome density

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On the other hand, the BMW (GLABRA3 [GL3]/enhancer of GLABRA3 [EGL3]-GLABRA1 [GL1]/TRANSPARENT TESTA G1-) complex regulates the initialization of trichome; GL3 and GL1 are induced by JA and increase the trichome number; however, JA activates GL1 in an indirect manner.[120] GL2 acts downstream of BMW, while it is still unknown what factors act downstream of GL2.

Stem cells are involved in cell differentiation and regulated by cyclin protein.[129] The cyclin proteins may act downstream of GL2 to modulate trichome development by regulating the mitotic cell cycle. Therefore, trichome initiation involves a progression of endoreduplication cycles, while the modulation of the cell cycle is unknown [Figure 11]a.

Gibberellins increase trichome number

Previous studies have indicated that GA is a hormone that is involved in trichome development as well.[114],[130],[131] The GA-deficient mutants ga1-3 do not produce GA or trichomes in the leaves. However, adding exogenous GA on ga1-3 may restore trichomes. When paclobutrazol or uniconazole was used to inhibit GA in ecotype Columbia (col), trichome initialization failed. GL1 is upregulated by GAs and inhibited in ga1-3.[132],[133] The mutant spy-5 (SPY is a RGA signaling pathway) has more trichome than col, and gl mutant is epistatic to the spy mutant, indicating that GL1 is downstream of GA signaling. SlbHLH95 negatively regulates trichome formation by inhibiting the expression of SlGA20ox2 and SlKS5 via direct binding to their promoters and leads to repressing GA content in tomato.[134] The C2H2 factor GIS may act downstream of GA to promote trichome development and is a direct target of GIS3 detected by ChIP analysis.[131],[135] Genetics information has indicated that GIS may act downstream of TCL1.[136] However, the relationship between GIS3 and TCL1 is still unknown. GIS acts upstream of BMW complex, and little is known about GIS directly targeting BMW complex.

In addition, both GIS2 and ZFP8 can regulate trichome development and be induced by GA as well.[137] More importantly, GIS2 and ZFP8 directly targeted by GIS3.[137] This suggests that GA-regulated trichome development is mainly mediated by C2H2 TFs.

Trichome development involves abscisic acid modulation of cuticular wax biosynthesis

Wax is an important component in trichome development. MYB106 expresses in the trichome and the mutant of MYB106 exhibited defects in cuticle development; at the same time, the trichome showed abnormalities. MYB106 positively modulates cuticle formation by activating cutin and wax biosynthetic genes mRNA level[138] and wax inducer1/SHINE1, which promotes cutin biosynthesis.[139] Knockdown the expression of AtMYB16 in Arabidopsis, the transgenic plants appear abnormal cuticle in trichome.[138] It suggests that MYB16 and MYB106 have redundant functions in cuticle-mediated trichome development. In addition, AaMIXTA1 increases the trichome number by enhancing cuticle load and enhancing cuticle relative gene expression in A. annua providing a link between cuticle formation and trichome development.[115]

MYB96, induced by ABA, is a transcription activator of long-chain fatty acid enzymes that acted in the cuticular wax biosynthesis by binding to the promoter of these genes.[140] Another gene, MYB41, is induced by ABA and acts as a negative role in cuticle biosynthesis.[141] The mechanism of MYB41 regulation of cuticle biosynthesis is still unknown. Therefore, a clear link between phytohormone and cuticular well established. However, the relationship among plant hormone regulation, cuticle loading, and trichome development is not clear and needs further study.


  Phytohormone-Mediated Transport of Secondary Metabolites Top


The secondary metabolites of plants called alkaloids, terpenoids, and phenolics are used to ward off pathogens or insects. These chemicals may be toxic to plants themselves, and plants cope with these compounds by transporting these chemicals to the cell surface or storing them in vacuoles or trichomes. There are several kinds of transporters in plants; the ABC transporters and multidrug and toxin extrusion transporters (MATEs) are important transporters for secondary metabolites. The transporters pleiotropic drug resistance 2 and lipid transfer protein 3 of A. annua can transport artemisinic acid (AA) and dihydroartemisinic acid in Nicotiana benthamiana leaves.[23]

The multidrug and toxin extrusion transporter 2 (MATE2) is an important transporter involved in flavonoid transport in Medicago truncatula.[14] TmHKT1;5-A is a Na+-selective transporter that increases leaf [Na+] and enhances wheat grain yield by 25%.[142] JA is an important plant hormone for resisting bacteria. To increase resistance to bacteria, NpPDR1 was induced by JA and transported the diterpene sclareol to enhance resistance to Botrytis cinerea.[143] Alkaloids are involved in the defense against pathogens and herbivores of Nicotiana species. Nicotine can be translocated from the root to the leaves by the tobacco alkaloid transporter 1, which is inducible by JA.[144] Another ABC transporter, CrTPT2, is induced by MJ and can transport catharanthine, which is used as an anticancer drug, in C. roseus.[145] However, the localization of the monoterpenoid indole alkaloids enzymes plays a decisive role in catharanthine biosynthesis, so it is unknown whether these enzymes are located on the plasma membrane or near the membrane. JA and catharanthine can induce the expression of CrTPT2 to transport catharanthine; therefore, some TFs may play central roles in activating the promoter of CrTPT2, such as ORCA2 and ORCA3, but this interesting hypothesis needs direct evidence in support.


  Phytohormones Modulation of Secondary Metabolite Mediated by Transcription Factors at the Transcriptional Level Top


Apetala2/ethylene responsive element binding protein transcription factors

The AP2/ERF family is a plant-specific TF that harbors a highly conserved region of approximately 60 amino acids. There are four major subfamilies: AP2, ERF, RAV, and dehydration-responsive element-binding protein subfamilies.[146] The ERF subfamily proteins bind DNA through the GCC-box sequence AGCCGCC, which is an essential sequence for binding.

JA is an important plant hormone that induces the biosynthesis of protective secondary metabolites. The AP2/ERF TF ORCA2 specifically binds to the GCC-box of strictosidine synthase (Str) and enhances Str at the transcriptional level, which was reported to result in an increase in the terpenoid indole alkaloid content in C. roseus.[147] ORCA3, another JA-induced AP2/ERF TF in C. roseus, not only directly regulated the expression level of Str and cytochrome P450-reductase (cpr) but also increased the mRNA level of the primary metabolite biosynthetic gene tryptophan decarboxylase.[148] In the artemisinin biosynthesis process, AaERF1 and AaERF2 are induced by JA and binds to the promoters of the artemisinin biosynthetic pathway genes ADS and amorphadiene 12-hydroxylase (CYP71AV1), enhancing the artemisinin content by enhancing ADS and CYP71AV1 expressions.[149] JA-induced AP2/ERF factors ORC1 and JAP1 in tobacco positively regulate the transcription of the nicotine biosynthetic pathway gene putrescine N-methyltransferase.[150] AP2/ERF factors are very important in secondary metabolic regulation, but what regulators are there to regulate these AP2/ERFs? Previous studies have indicated that mitogen-activated protein kinase 3 (MPK3) and MPK6 phosphorylate ERF6 on the C-terminal Ser-Pro sites to enhance its protein stability in vivo.[151] Teosinte branched 1/cycloidea/proliferating cell factor 14 may modulate the activation activity of octadecanoid-responsive AP2/ERF in A. annua to increase artemisinin biosynthesis.[152]

AP2/ERF TFs play an important role in secondary metabolites biosynthesis in plants.[153],[154] However, the overexpression of one single AP2/ERF may not improve many secondary metabolites because secondary metabolism regulation is a complex network. Therefore, screening AP2/ERF interacting proteins or target genes is the focus of current research.

Basic helix–loop–helix transcription factors

bHLH TFs play an important role in modulating secondary metabolism in plants. bHLH TFs consist of two highly conserved domains for DNA binding (bind to a consensus hexanucleotide E-box, CANNTG) and protein–protein interaction (form homodimers or heterodimers). The bHLH signature domain comprises approximately 50–60 amino acid residues.

bHLH TFs have an important role in the regulation of anthocyanin.[155],[156],[157] Recent studies also indicated that bHLH TFs may modulate terpene metabolites. BIS1, a bHLH TF, was reported to be induced by JA and played a complementary role to ORCA3.[148],[158] It is not clear whether BIS1 directly binds to the promoter of monoterpenoid indole alkaloid biosynthetic pathway genes. However, it can activate iridoid gene expression. In addition, in the network of monoterpenoid indole alkaloid biosynthesis, many genes regulate monoterpenoid indole alkaloids, while the modulation of BIS1 is still unknown.[159] Both AaMYC2 in A. annua and MYC2 in Arabidopsis affects terpene biosynthesis by increasing terpene biosynthetic pathway gene expression;[105],[160] however, the regulation of MYC2 expression requires further study.

Basic leucine zipper transcription factors

The basic leucine zipper (bZIP) family occurs in all eukaryotes. In plants, bZIP TFs play key roles in seed formation, morphogenesis, flower development, stress responses, pathogen defense, and secondary metabolism.[161] The bZIP proteins are subdivided into ten groups, i.e., A, B, C, D, E, F, G, H, I, and S. The bZIP domain consists of two parts: a basic region of approximately 16 amino acids, with a nuclear localization signal, and an N-x7-R/K motif involved in DNA binding, with an amphipathic helix. bZIP proteins can specifically bind to DNA sequences with the “ACGT” core, such as “TACGTA” (A-box), “GACGTC” (C-box), and “CACGTG” (G-box).[162],[163]

The bZIP TFs play an important role in regulating secondary metabolites in plants.[164],[165] Recent studies suggest that secondary metabolites are associated with independent bZIP TFs and may depend on phytohormone signaling processes. In A. annua, the ABA pathway gene AaBZIP1 enhances the artemisinin content by activating the expression of the artemisinin biosynthetic pathway genes ADS and CYP71AV1.[101] AaTGA6, another Bzip TF, can interact with AaNPR1 to enhance the expression of AaERF1, which is a positive factor for activation of mRNA of ADS and CYP71AV1, thus improving artemisinin by enhancing gene expression.[166] HY5, a bzip TF induced by ABA, regulates anthocyanin accumulation via the repression of MYBL2, activation of MYB75, or direct binding to the promoter of anthocyanin biosynthetic genes.[167],[168],[169],[170]

MYB transcription factors

The MYB TF family is large and functionally diverse in plants, animals, and microbes. In plants, MYB TFs play a key role in the modulation of secondary metabolites.[171],[172] Most MYBs are sequence-specific DNA-binding proteins that act as a mediator between DNA elements and the regulatory protein network. The MYB domain is highly conserved, which consists of four basic amino acid sequence repeats (R) (approximately 52 amino acids). According to the number of repeats, the MYB proteins can be divided into four classes: 1R-MYB, R2R3-MYB, 3R-MYB, and 4R-MYB.[173] MYBs recognize MBSI (CNGTTR), MBSII (GKTWGTTR), and variants of the MBSIIG (GKTWGGTR; R, A or G; K, G or T; W, A or T).[163],[174]

MYB TFs are involved in almost every type of plant secondary metabolism.[175],[176] GA promotes the conversion of artemisinic acid to artemisinin and enhances trichome density in A. annua.[130],[177] AaMYB61 is the key regulator of GA biosynthesis. It acts as a key component, promoting artemisinin biosynthesis by increasing the expressions of ADS and CYP71AV1, activating the trichome initial, and leading to an enhanced artemisinin content.[178] Similar to these functions, another MYB TF, AaMIXTA1, is induced by MJ.[115] However, MYBL is involved in anthocyanin biosynthesis by interacting with GA and JA.[179] SmMYB9b enhances the content of tanshinones in S. miltiorrhiza by increasing the mRNA levels of SmDXS2, SmDXR, SmGGPPS, and SmKSL1. In addition, SmMYB9b is induced by ABA, GA, and MeJA; therefore, it may be the hub of phytohormone crosstalk.[180] Thus, the regulatory network of phytohormone modulation of secondary metabolism involving MYB TFs may be far more intricate than we thought.

SQUAMOSA-promoter binding protein-like transcription factors

SQUAMOSA-promoter binding protein-like (SPL) proteins occur in all plants and were first isolated from Antirrhinum majus and found to regulate flower development by binding to the promoter of the floral meristem identity gene SQUAMOSA. The conserved SBP domain consists of 76 amino acids and is responsible for the recognition of the SBP-box “GTAC.” The SPL proteins have recently been divided into eight (I–VIII) major clades, most of which play a major role in vegetable phase changes, flowering time regulation and branching modulation.[181]

GA may affect secondary metabolites, such as artemisinin and anthocyanin.[177],[182] The GA signaling pathway TF DELLAs interact with SPL9, which regulates anthocyanin biosynthesis by binding to the promoter of dihydroflavonol reductase.[183] Moreover, SPL9 directly binds to the promoter of TPS21, which is a key gene encoding β-caryophyllene.[184] AaSPL2 can activate the promoter of the artemisinin biosynthetic pathway gene DBR2, enhancing the artemisinin content.[185]

WRKY transcription factors

The WRKY family is a large family in plants that are involved in the modulation of plant immunity, secondary metabolites, and biotic stress. The WRKY domain is approximately 60 residues. The WRKY TFs are divided into groups I, IIa + IIb, IIc, IId + IIe, and III according to phylogenetics.[186] The WRKY domain specifically binds to the W box (TTGACC/T), and the GKK motif of the WRKY domain plays a central role in binding site recognition.[187]

In general, overexpression of TFs may be a promising approach to increase the secondary metabolic content. TFs exert their functions by binding to the promoter of the target gene, thereby negatively or positively modulating gene expression. Many individual WRKY TFs have been identified to play an important role in regulating and fine-tuning secondary metabolites. Cadinene synthase (CAD1) functions as a sesquiterpene cyclase that catalyzes the first step of gossypol biosynthesis in Gossypium arboretum. GaWRKY1 has similar expression patterns to CAD1, and both are induced by MJ. GaWRKY1 regulates the gossypol content by directly binding to the promoter of CAD1.[188] A C. roseus TF CrWRKY1, induced by jasmonate, positively modulates terpenoid indole alkaloids by binding to the promoter of tryptophan decarboxylase.[189],[190] Artemisia glandular trichome-specific WRKY 1, a WRKY TF, induced by ABA and MJ, positively modulates the artemisinin content by activating the expression of the artemisinin biosynthetic pathway genes.[191] Another artemisinin biosynthesis-related gene, AaWRKY1, interacts with JA and enhances the artemisinin content by binding to the promoter of ADS.[192]


  Phytohormones Modulation of Secondary Metabolite Mediated by MicroRNA and Protein Kinase at the Posttranslational Level Top


MicroRNA mediates posttranscriptional regulation of secondary metabolites

MicroRNA (miRNA), a type of endogenous noncoding single-stranded RNA, is usually 19–25 nucleotides in length and plays a central role in posttranscriptional gene regulation by translational repression or degradation of target genes.[193] miRNAs are involved in numerous important biological processes in plants, such as growth and development, flowering, secondary metabolism regulation, and biomass accumulation.[194],[195],[196] Plant hormones may interact with miRNAs and regulate secondary metabolism biosynthesis.

Previously, miR393 was reported to be involved in secondary metabolism biosynthesis, enhancing SA signaling and playing an important role in re-directing secondary metabolite flow toward camalexin for glucosinolates.[197] miR156 is highly conserved in plants and plays a crucial role in regulating trichome development, biomass, and yield flowering.[194],[195],[196],[198],[199] The miR156-SPL9 model plays a crucial role in regulating secondary metabolism, e.g., anthocyanins and sesquiterpenes.[183],[184] SPL9 can interact with JAZ3 in Arabidopsis and can regulate the JA response.[200] miR156 exerts a negative effect on the accumulation of SPL9 and exhibits an increased JA response.

miR319 is a major miRNA that modulates lateral organ development and interacts with ABA and JA.[201],[202] TCP3, the target of miR319, functions as an important regulator of flavonoid biosynthesis by interacting with R2R3–MYB proteins.[203] R2R3–MYB proteins modulate flavonoid biosynthetic steps by forming ternary WD40/bHLH/R2R3–MYB (BMW) complexes.[156]

Protein kinase-mediated regulation of secondary metabolites

Protein kinases may play a central role in signal transduction, and their interactions are crucial for plant growth and development. Protein kinases can modulate various biological processes in plants, including cell expansion, innate immunity, abiotic stresses, and plant hormone signaling.[151],[204],[205],[206],[207],[208] Protein kinases can regulate secondary metabolites at the posttranslational level. In Arabidopsis, camalexin is defined as an antimicrobial compound involved in resistance against pathogens, and its content is regulated by the MPK3/MPK6 cascade.[209] MPK3/MPK6 modulates the camalexin content by phosphorylating WRKY33, which directly binds to camalexin by binding to the promoter of CYP71B15.[205] MPK4 modulates plant immunity and phytohormone responses in Arabidopsis; its phosphorylation of MYB75, an R2R3 MYB TF, increases the stability of MYB75 and enhances anthocyanin accumulation.[208]

Phytohormones play an important role in the modulation of protein kinase mRNA levels. In C. roseus, CrMPK3 is activated by MeJA, increasing the expression levels of key alkaloid biosynthesis pathway genes and the accumulation of alkaloids.[210] A recent study indicated that CrMAPKK1 acts upstream of CrMPK3 to regulate alkaloid modulators, such as ORCA3, ORCA4, and ORCA5, which affect the expression of alkaloid pathway genes.[159] An ABA-responsive kinase (AaAPK1), induced by ABA, is involved in modulating artemisinin biosynthesis by interacting with the artemisinin biosynthesis regulator AabZIP1.[102] ORC1 and bHLH1 are important TFs that modulate nicotine biosynthesis in Nicotiana tabacum.[150],[211] A JA-induced mitogen-activated protein kinase in N. tabacum, MAPKK1 (JAM1), was identified that regulates the activity of both ORC1 and bHLH1 proteins and enhances nicotine biosynthesis.[150]


  Conclusion Top


Recent advances in phytohormone studies have provided new insights into the significance of phytohormones as key players in modulating secondary metabolites via TFs, miRNAs, trichomes, transporters, and protein kinases. In particular, the roles of phytohormones mediating secondary metabolites by TFs, miRNAs, trichomes, transporters, and protein kinases have been identified, and the underlying mechanisms have been uncovered. Therefore, these results can aid in the understanding of the modulation of secondary metabolism biosynthesis, transportation, accumulation, and release by phytohormones.

Despite recent progress in defining the phytohormones controlling secondary metabolism, some questions remain open, such as what are the main factors (e.g., TFs, miRNAs, trichomes, transporters, and protein kinases) that enhance the yield of secondary metabolites? What types of phytohormone signaling pathway crosstalks affect the induction of secondary metabolite accumulation? What are the underlying principles of the properties of the phytohormones that mediate the secondary metabolite network?

A deeper understanding of the relationship between factors and phytohormones requires various reliable approaches using systems omics (transcriptomics, metabolomics, and proteomics) combined with bioinformatics. In addition, a method for fast and reliable detection of gene function should be devised.

Acknowledgments

Nil.

Financial support and sponsorship

This work was funded by the National Key R&D Program of China (2019YFC1711000), the National Science and Technology Major Project (2017ZX09101002-003-002), the Shanghai Rising-Star Program (18QB1402700, China), Shanghai local Science and Technology Development Fund Program guided by the Central Government (YDZX20203100002948), the Shanghai Natural Science Foundation in China (20ZR1453800), and the National Natural Science Foundation of China (32070332, 81673550, 81874335).

Conflicts of interest

Prof. Wan-Sheng Chen is an editorial Board member of World Journal of Traditional Chinese Medicine. The article was subject to the journal's standard procedures, with peer review handled independently of this editorial board member and their research groups.



 
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]


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