Discovery of ElABCG39: a key player in ingenol transmembrane efflux identified through genome-wide analysis of ABC transporters in Euphorbia lathyris L.
Euphorbia lathyris L.
ABC transporter
Ingenol
Pleiotropic drug resistance (PDR) transporter
Transport inhibition
Journal
Plant cell reports
ISSN: 1432-203X
Titre abrégé: Plant Cell Rep
Pays: Germany
ID NLM: 9880970
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
23
07
2024
accepted:
16
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Based on transport inhibition and genome-wide analysis, 123 ABC transporters of Euphorbia lathyris were identified, and it was found that the PDR family members ElABCG39 mediated ingenol efflux. Identification of ingenol biosynthetic enzymes and transporters in plant is fundamental to realize its biosynthesis in chassis cells. At present, several key enzymes of the ingenol biosynthesis pathway have been identified, while the mechanisms governing the accumulation or transport of ingenol to distinct plant tissue compartments remain elusive. In this study, transport inhibition analyses were performed, along with genome-wide identification of 123 genes encoding ABC proteins in Euphorbia lathyris L., eventually discovering that a PDR transporter ElABCG39 mediates ingenol transmembrane transport and is localized on the plasma membrane. Expression of this protein in yeast AD1-8 promoted the transmembrane efflux of ingenol with strong substrate specificity. Furthermore, in ElABCG39 RNAi transgenic hairy roots, ingenol transmembrane efflux was significantly reduced and hairy root growth was inhibited. The discovery of the first Euphorbia macrocyclic diterpene transporter ElABCG39 has not only further improved the ingenane diterpenoid biosynthesis regulatory network, but also provided a new key element for ingenol production in chassis cells.
Identifiants
pubmed: 39470817
doi: 10.1007/s00299-024-03361-1
pii: 10.1007/s00299-024-03361-1
doi:
Substances chimiques
Diterpenes
0
Plant Proteins
0
ATP-Binding Cassette Transporters
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
274Subventions
Organisme : National Natural Science Foundation of China
ID : 32270404
Organisme : Natural Science Foundation of Jiangsu Province
ID : BK20242010
Organisme : Jiangsu Provincial Key Research and Development Program
ID : BE2022370
Organisme : Agricultural Science and Technology Independent Innovation Fund Project of Jiangsu Province
ID : CX (22)3068
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Adebesin F, Widhalm JR, Boachon B, Lefevre F, Pierman B, Lynch JH, Alam I, Junqueira B, Benke R, Ray S, Porter JA, Yanagisawa M, Wetzstein HY, Morgan JA, Boutry M, Schuurink RC, Dudareva N (2017) Emission of volatile organic compounds from petunia flowers is facilitated by an abc transporter. Science 356(6345):1386–1388
pubmed: 28663500
doi: 10.1126/science.aan0826
Appendino G (2016) Ingenane diterpenoids. Prog Chem Org Nat Prod 102:1–90
pubmed: 27380406
Appendino G, Tron GC, Cravotto G, Palmisano G, Jakupovic J (1999) An expeditious procedure for the isolation of ingenol from the seeds of euphorbia lathyris. J Nat Prod 62(1):76–79
pubmed: 9917286
doi: 10.1021/np980218n
Bailey TL, Johnson J, Grant CE, Noble WS (2015) The Meme Suite. Nucl Acids Res 43(W1):W39–W49
pubmed: 25953851
pmcid: 4489269
doi: 10.1093/nar/gkv416
Behrens CE, Smith KE, Iancu CV, Choe JY, Dean JV (2019) Transport of anthocyanins and other flavonoids by the arabidopsis atp-binding cassette transporter atabcc2. Sci Rep 9(1):437
pubmed: 30679715
pmcid: 6345954
doi: 10.1038/s41598-018-37504-8
Beis K (2015) Structural basis for the mechanism of abc transporters. Biochem Soc Trans 43(5):889–893
pubmed: 26517899
doi: 10.1042/BST20150047
Campbell EJ, Schenk PM, Kazan K, Penninckx IA, Anderson JP, Maclean DJ, Cammue BP, Ebert PR, Manners JM (2003) Pathogen-responsive expression of a putative atp-binding cassette transporter gene conferring resistance to the diterpenoid sclareol is regulated by multiple defense signaling pathways in arabidopsis. Plant Physiol 133(3):1272–1284
pubmed: 14526118
pmcid: 281622
doi: 10.1104/pp.103.024182
Carqueijeiro I, Noronha H, Duarte P, Geros H, Sottomayor M (2013) Vacuolar transport of the medicinal alkaloids from catharanthus roseus is mediated by a proton-driven antiport. Plant Physiol 162(3):1486–1496
pubmed: 23686419
pmcid: 3707533
doi: 10.1104/pp.113.220558
Chen PX, Li LW, Xu S, Zhang GD, Feng X, Wang QZ, Guan FQ, Chen Y (2024) Four lathyrane diterpenoids from the seeds of euphorbia lathyris. Fitoterapia 175:105965
pubmed: 38631599
doi: 10.1016/j.fitote.2024.105965
Czechowski T, Forestier E, Swamidatta SH, Gilday AD, Cording A, Larson TR, Harvey D, Li Y, He Z, King AJ, Brown GD, Graham IA (2022) Gene discovery and virus-induced gene silencing reveal branched pathways to major classes of bioactive diterpenoids in euphorbia peplus. Proc Natl Acad Sci U S A 119(21):e2091077177
doi: 10.1073/pnas.2203890119
de Almeida NP, Neto D, Carneiro G, de Farias A, Domont GB, de Paiva CF, Nogueira F (2021) Monitoring casbene synthase in jatropha curcas tissues using targeted proteomics. Plant Methods 17(1):15
pubmed: 33549129
pmcid: 7868020
doi: 10.1186/s13007-021-00716-7
Decottignies A, Grant AM, Nichols JW, de Wet H, McIntosh DB, Goffeau A (1998) Atpase and multidrug transport activities of the overexpressed yeast abc protein yor1p. J Biol Chem 273(20):12612–12622
pubmed: 9575223
doi: 10.1074/jbc.273.20.12612
Edgar RC (2004) Muscle: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32(5):1792–1797
pubmed: 15034147
pmcid: 390337
doi: 10.1093/nar/gkh340
Fetsch EE, Davidson AL (2002) Vanadate-catalyzed photocleavage of the signature motif of an atp-binding cassette (abc) transporter. Proc Natl Acad Sci U S A 99(15):9685–9690
pubmed: 12093921
pmcid: 124977
doi: 10.1073/pnas.152204499
Frangne N, Eggmann T, Koblischke C, Weissenbock G, Martinoia E, Klein M (2002) Flavone glucoside uptake into barley mesophyll and arabidopsis cell culture vacuoles. Energization occurs by h(+)-antiport and atp-binding cassette-type mechanisms. Plant Physiol 128(2):726–733
pubmed: 11842175
pmcid: 148933
doi: 10.1104/pp.010590
Fu X, Shi P, He Q, Shen Q, Tang Y, Pan Q, Ma Y, Yan T, Chen M, Hao X, Liu P, Li L, Wang Y, Sun X, Tang K (2017) Aapdr3, a pdr transporter 3, is involved in sesquiterpene beta-caryophyllene transport in artemisia annua. Front Plant Sci 8:723
pubmed: 28533790
pmcid: 5420590
doi: 10.3389/fpls.2017.00723
Fu X, Liu H, Hassani D, Peng B, Yan X, Wang Y, Wang C, Li L, Liu P, Pan Q, Zhao J, Qian H, Sun X, Tang K (2020) Aaabcg40 enhances artemisinin content and modulates drought tolerance in artemisia annua. Front Plant Sci 11:950
pubmed: 32676091
pmcid: 7333515
doi: 10.3389/fpls.2020.00950
Gani U, Vishwakarma RA, Misra P (2021) Membrane transporters: the key drivers of transport of secondary metabolites in plants. Plant Cell Rep 40(1):1–18
pubmed: 32959124
doi: 10.1007/s00299-020-02599-9
Gemmer M, Chaillet ML, van Loenhout J, Cuevas AR, Vismpas D, Grollers-Mulderij M, Koh FA, Albanese P, Scheltema RA, Howes SC, Kotecha A, Fedry J, Forster F (2023) Visualization of translation and protein biogenesis at the er membrane. Nature 614(7946):160–167
pubmed: 36697828
pmcid: 9892003
doi: 10.1038/s41586-022-05638-5
Grec S, Vanham D, de Ribaucourt JC, Purnelle B, Boutry M (2003) Identification of regulatory sequence elements within the transcription promoter region of npabc1, a gene encoding a plant abc transporter induced by diterpenes. Plant J 35(2):237–250
pubmed: 12848828
doi: 10.1046/j.1365-313X.2003.01792.x
Hasan A, Tang D, Nijat D, Yang H, Aisa HA (2021) Diterpenoids from euphorbia glomerulans with potential reversal activities against p-glycoprotein-mediated multidrug resistance. Bioorg Chem 117:105442
pubmed: 34742027
doi: 10.1016/j.bioorg.2021.105442
Held K, Pascaud F, Eckert C, Gajdanowicz P, Hashimoto K, Corratge-Faillie C, Offenborn JN, Lacombe B, Dreyer I, Thibaud JB, Kudla J (2011) Calcium-dependent modulation and plasma membrane targeting of the akt2 potassium channel by the cbl4/cipk6 calcium sensor/protein kinase complex. Cell Res 21(7):1116–1130
pubmed: 21445098
pmcid: 3193494
doi: 10.1038/cr.2011.50
Higgins CF (1992) Abc transporters: from microorganisms to man. Annu Rev Cell Biol 8:67–113
pubmed: 1282354
doi: 10.1146/annurev.cb.08.110192.000435
Higgins CF, Linton KJ (2004) The atp switch model for abc transporters. Nat Struct Mol Biol 11(10):918–926
pubmed: 15452563
doi: 10.1038/nsmb836
Jiang Q, Li K, Lu WJ, Li S, Chen X, Liu XJ, Yuan J, Ding Q, Lan F, Cai SQ (2018) Identification of small-molecule ion channel modulators in C. elegans channelopathy models. Nat Commun 9(1):3941
pubmed: 30258187
pmcid: 6158242
doi: 10.1038/s41467-018-06514-5
Jiang M, Xue Y, Li J, Rao K, Yan S, Li H, Chen X, Li R, Liu D (2021) Pkcdelta/mapks and nf-kappab pathways are involved in the regulation of ingenane-type diterpenoids from euphorbia neriifolia on macrophage function. J Inflamm Res 14:2681–2696
pubmed: 34234502
pmcid: 8243765
doi: 10.2147/JIR.S306846
Kato K, Horiba A, Hayashi H, Mizukami H, Terasaka K (2022) Characterization of triterpene saponin glycyrrhizin transport by glycyrrhiza glabra. Plants (Basel) 11(9):1250
pubmed: 35567251
Kostovic KGSJ (2017) Topical ingenol mebutate: a new treatment modality for multiple actinic keratoses and field cancerization. Anti-Cancer Agents Med Chem 17:1304–1311
doi: 10.2174/1871520617666170213130523
Krattinger SG, Lagudah ES, Spielmeyer W, Singh RP, Huerta-Espino J, McFadden H, Bossolini E, Selter LL, Keller B (2009) A putative abc transporter confers durable resistance to multiple fungal pathogens in wheat. Science 323(5919):1360–1363
pubmed: 19229000
doi: 10.1126/science.1166453
Lars Jørgensen SJM (2013) 14-step synthesis of (+)-ingenol from (+)-3-carene. Science 341(6148):878–882
pubmed: 23907534
doi: 10.1126/science.1241606
Lefevre F, Boutry M (2018) Towards identification of the substrates of atp-binding cassette transporters. Plant Physiol 178(1):18–39
pubmed: 29987003
pmcid: 6130012
Li L, Huang J, Lyu H, Guan F, Li P, Tian M, Xu S, Zhao X, Liu F, Paetz C, Feng X, Chen Y (2021) Two lathyrane diterpenoid stereoisomers containing an unusual trans-gem-dimethylcyclopropane from the seeds of euphorbia lathyris. RSC Adv 11(5):3183–3189
pubmed: 35424221
pmcid: 8694010
doi: 10.1039/D0RA10724G
Liu Z, Ding Z, Chen K, Xu M, Yu T, Tong G, Zhang H, Li P (2021) Balancing skeleton and functional groups in total syntheses of complex natural products: a case study of tigliane, daphnane and ingenane diterpenoids. Nat Prod Rep 38(9):1589–1617
pubmed: 33508045
doi: 10.1039/D0NP00086H
Luo D, Callari R, Hamberger B, Wubshet SG, Nielsen MT, Andersen-Ranberg J, Hallstrom BM, Cozzi F, Heider H, Lindberg MB, Staerk D, Hamberger B (2016) Oxidation and cyclization of casbene in the biosynthesis of euphorbia factors from mature seeds of euphorbia lathyris l. Proc Natl Acad Sci U S A 113(34):E5082–E5089
pubmed: 27506796
pmcid: 5003294
doi: 10.1073/pnas.1607504113
Nguyen VN, Moon S, Jung KH (2014) Genome-wide expression analysis of rice abc transporter family across spatio-temporal samples and in response to abiotic stresses. J Plant Physiol 171(14):1276–1288
pubmed: 25014263
doi: 10.1016/j.jplph.2014.05.006
Pierman B, Toussaint F, Bertin A, Levy D, Smargiasso N, De Pauw E, Boutry M (2017) Activity of the purified plant abc transporter ntpdr1 is stimulated by diterpenes and sesquiterpenes involved in constitutive and induced defenses. J Biol Chem 292(47):19491–19502
pubmed: 28972149
pmcid: 5702685
doi: 10.1074/jbc.M117.811935
Prieto D, Corchete P (2014) Transport of flavonolignans to the culture medium of elicited cell suspensions of silybum marianum. J Plant Physiol 171(2):63–68
pubmed: 24331420
doi: 10.1016/j.jplph.2013.10.005
Ricigliano VA, Sica VP, Knowles SL, Diette N, Howarth DG, Oberlies NH (2020) Bioactive diterpenoid metabolism and cytotoxic activities of genetically transformed euphorbia lathyris roots. Phytochemistry 179:112504
pubmed: 32980713
pmcid: 7863580
doi: 10.1016/j.phytochem.2020.112504
Ro DK, Ouellet M, Paradise EM, Burd H, Eng D, Paddon CJ, Newman JD, Keasling JD (2008) Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid. BMC Biotechnol 8:83
pubmed: 18983675
pmcid: 2588579
doi: 10.1186/1472-6750-8-83
Sanchez-Fernandez R, Davies TG, Coleman JO, Rea PA (2001) The arabidopsis thaliana abc protein superfamily, a complete inventory. J Biol Chem 276(32):30231–30244
pubmed: 11346655
doi: 10.1074/jbc.M103104200
Shi M, Liao P, Nile SH, Georgiev MI, Kai G (2021) Biotechnological exploration of transformed root culture for value-added products. Trends Biotechnol 39(2):137–149
pubmed: 32690221
doi: 10.1016/j.tibtech.2020.06.012
Shitan N, Bazin I, Dan K, Obata K, Kigawa K, Ueda K, Sato F, Forestier C, Yazaki K (2003) Involvement of cjmdr1, a plant multidrug-resistance-type atp-binding cassette protein, in alkaloid transport in coptis japonica. Proc Natl Acad Sci U S A 100(2):751–756
pubmed: 12524452
pmcid: 141068
doi: 10.1073/pnas.0134257100
Srinivasan P, Smolke CD (2020) Biosynthesis of medicinal tropane alkaloids in yeast. Nature 585(7826):614–619
pubmed: 32879484
pmcid: 7529995
doi: 10.1038/s41586-020-2650-9
Srinivasan P, Smolke CD (2021) Engineering cellular metabolite transport for biosynthesis of computationally predicted tropane alkaloid derivatives in yeast. Proc Natl Acad Sci U S A 118(25):e2104460118
pubmed: 34140414
pmcid: 8237673
doi: 10.1073/pnas.2104460118
Stukkens Y, Bultreys A, Grec S, Trombik T, Vanham D, Boutry M (2005) Nppdr1, a pleiotropic drug resistance-type atp-binding cassette transporter from nicotiana plumbaginifolia, plays a major role in plant pathogen defense. Plant Physiol 139(1):341–352
pubmed: 16126865
pmcid: 1203383
doi: 10.1104/pp.105.062372
Theodoulou FL, Kerr ID (2015) Abc transporter research: going strong 40 years on. Biochem Soc Trans 43(5):1033–1040
pubmed: 26517919
pmcid: 4652935
doi: 10.1042/BST20150139
Trott O, Olson AJ (2010) Autodock vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461
pubmed: 19499576
pmcid: 3041641
doi: 10.1002/jcc.21334
van den Brule S, Muller A, Fleming AJ, Smart CC (2002) The abc transporter sptur2 confers resistance to the antifungal diterpene sclareol. Plant J 30(6):649–662
pubmed: 12061897
doi: 10.1046/j.1365-313X.2002.01321.x
Verrier PJ, Bird D, Burla B, Dassa E, Forestier C, Geisler M, Klein M, Kolukisaoglu U, Lee Y, Martinoia E, Murphy A, Rea PA, Samuels L, Schulz B, Spalding EJ, Yazaki K, Theodoulou FL (2008) Plant abc proteins–a unified nomenclature and updated inventory. Trends Plant Sci 13(4):151–159
pubmed: 18299247
doi: 10.1016/j.tplants.2008.02.001
Wang F, Zhao W, Lv W, Li P, Tian M, Xu S, Li L, Wang R, Liu F, Chen Y, Feng X (2023) Identification and functional characterization of a novel sinapyl alcohol acyltransferase from euphorbia lathyris l. J Agric Food Chem 71(50):20187–20197
pubmed: 38044624
doi: 10.1021/acs.jafc.3c07127
Wang Y, Xu S, Zhang G, Li P, Liu C, Zhou J, Feng X, Li L, Chen Y (2024) Targeted discovery of unusual diterpenoids with anti-fungal activity from the root of euphorbia lathyris. Phytochemistry 225:114193
pubmed: 38908463
doi: 10.1016/j.phytochem.2024.114193
Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer T, Rempfer C, Bordoli L, Lepore R, Schwede T (2018) Swiss-model: homology modelling of protein structures and complexes. Nucleic Acids Res 46(W1):W296–W303
pubmed: 29788355
pmcid: 6030848
doi: 10.1093/nar/gky427
Wong J, de Rond T, D’Espaux L, van der Horst C, Dev I, Rios-Solis L, Kirby J, Scheller H, Keasling J (2018) High-titer production of lathyrane diterpenoids from sugar by engineered saccharomyces cerevisiae. Metab Eng 45:142–148
pubmed: 29247866
doi: 10.1016/j.ymben.2017.12.007
Yan C, Duan W, Lyu S, Li Y, Hou X (2017) Genome-wide identification, evolution, and expression analysis of the atp-binding cassette transporter gene family in brassica rapa. Front Plant Sci 8:349
pubmed: 28367152
pmcid: 5355449
doi: 10.3389/fpls.2017.00349
Ya-Si Huang YLCC (2019) Potent anti-hiv ingenane diterpenoids from euphorbia ebracteolata. J Nat Prod 82(6):1587–1592
pubmed: 31184480
doi: 10.1021/acs.jnatprod.9b00088
Zhang J, Hansen LG, Gudich O, Viehrig K, Lassen L, Schrubbers L, Adhikari KB, Rubaszka P, Carrasquer-Alvarez E, Chen L, D’Ambrosio V, Lehka B, Haidar AK, Nallapareddy S, Giannakou K, Laloux M, Arsovska D, Jorgensen M, Chan L, Kristensen M, Christensen HB, Sudarsan S, Stander EA, Baidoo E, Petzold CJ, Wulff T, O’Connor SE, Courdavault V, Jensen MK, Keasling JD (2022) A microbial supply chain for production of the anti-cancer drug vinblastine. Nature 609(7926):341–347
pubmed: 36045295
pmcid: 9452304
doi: 10.1038/s41586-022-05157-3
Zhao WPJWF (2022) Integrating metabolomics and transcriptomics to unveil the spatiotemporal distribution of macrocyclic diterpenoids and candidate genes involved in ingenol biosynthesis in the medicinal plant euphorbia lathyris l. Ind Crop Prod 184:115096
doi: 10.1016/j.indcrop.2022.115096
Zhao W, Huang L, Xu S, Wu J, Wang F, Li P, Li L, Tian M, Feng X, Chen Y (2024) Identification of one o-methyltransferase gene involved in methylated flavonoid biosynthesis related to the uv-b irradiation response in euphorbia lathyris. Int J Mol Sci 25(2):782
pubmed: 38255854
pmcid: 10815478
doi: 10.3390/ijms25020782
Zhiyi N, Guijuan K, Yu L, Longjun D, Rizhong Z (2015) Whole-transcriptome survey of the putative atp-binding cassette (abc) transporter family genes in the latex-producing laticifers of hevea brasiliensis. PLoS ONE 10(1):e116857
doi: 10.1371/journal.pone.0116857
Zhu A, Zhang T, Wang Q (2018) The phytochemistry, pharmacokinetics, pharmacology and toxicity of euphorbia semen. J Ethnopharmacol 227:41–55
pubmed: 30144497
doi: 10.1016/j.jep.2018.08.024