{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T13:48:44Z","timestamp":1789652924628,"version":"4.0.0"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T00:00:00Z","timestamp":1708992000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T00:00:00Z","timestamp":1708992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072302"],"award-info":[{"award-number":["82072302"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in a <jats:italic>Plasmodium<\/jats:italic> de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the <jats:italic>Plasmodium yoelii<\/jats:italic> UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the <jats:italic>P. yoelii<\/jats:italic> multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates\/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.<\/jats:p>","DOI":"10.1038\/s41467-024-46006-3","type":"journal-article","created":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T09:02:18Z","timestamp":1709024538000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3080-7825","authenticated-orcid":false,"given":"Ruixue","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhen","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxu","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuezhou","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luming","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengfa","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9354-5864","authenticated-orcid":false,"given":"Xianming","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8907-9143","authenticated-orcid":false,"given":"Jing","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-zhuan","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6397-2785","authenticated-orcid":false,"given":"Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,27]]},"reference":[{"key":"46006_CR1","unstructured":"WHO. World Malaria Report 2023. (Geneva: WHO press)."},{"key":"46006_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11553","volume":"7","author":"MI Veiga","year":"2016","unstructured":"Veiga, M. I. et al. Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nat. Commun. 7, 11553 (2016).","journal-title":"Nat. Commun."},{"key":"46006_CR3","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1038\/35002615","volume":"403","author":"MB Reed","year":"2000","unstructured":"Reed, M. B., Saliba, K. J., Caruana, S. R., Kirk, K. & Cowman, A. F. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403, 906\u2013909 (2000).","journal-title":"Nature"},{"key":"46006_CR4","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1086\/507115","volume":"194","author":"ABS Sidhu","year":"2006","unstructured":"Sidhu, A. B. S. et al. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J. Infect. Dis. 194, 528\u2013535 (2006).","journal-title":"J. Infect. Dis."},{"key":"46006_CR5","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/S0140-6736(04)16767-6","volume":"364","author":"RN Price","year":"2004","unstructured":"Price, R. N. et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364, 438\u2013447 (2004).","journal-title":"Lancet"},{"key":"46006_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2017.31","volume":"2","author":"W Wong","year":"2017","unstructured":"Wong, W. et al. Mefloquine targets the Plasmodium falciparum 80S ribosome to inhibit protein synthesis. Nat. Microbiol. 2, 17031 (2017).","journal-title":"Nat. Microbiol."},{"key":"46006_CR7","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1016\/j.tips.2006.09.005","volume":"27","author":"SG Valderramos","year":"2006","unstructured":"Valderramos, S. G. & Fidock, D. A. Transporters involved in resistance to antimalarial drugs. Trends Pharm. Sci. 27, 594\u2013601 (2006).","journal-title":"Trends Pharm. Sci."},{"key":"46006_CR8","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1083\/jcb.113.5.1033","volume":"113","author":"AF Cowman","year":"1991","unstructured":"Cowman, A. F., Karcz, S., Galatis, D. & Culvenor, J. G. A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. J. Cell Biol. 113, 1033\u20131042 (1991).","journal-title":"J. Cell Biol."},{"key":"46006_CR9","doi-asserted-by":"publisher","first-page":"3000","DOI":"10.1038\/sj.emboj.7601203","volume":"25","author":"P Rohrbach","year":"2006","unstructured":"Rohrbach, P. et al. Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum. EMBO J. 25, 3000\u20133011 (2006).","journal-title":"EMBO J."},{"key":"46006_CR10","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1111\/j.1349-7006.2007.00538.x","volume":"98","author":"Y Kimura","year":"2007","unstructured":"Kimura, Y., Morita, S.-y, Matsuo, M. & Ueda, K. Mechanism of multidrug recognition by MDR1\/ABCB1. Cancer Sci. 98, 1303\u20131310 (2007).","journal-title":"Cancer Sci."},{"key":"46006_CR11","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1126\/science.aar7389","volume":"359","author":"Y Kim","year":"2018","unstructured":"Kim, Y. & Chen, J. Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science 359, 915\u2013919 (2018).","journal-title":"Science"},{"key":"46006_CR12","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/j.1365-2958.2007.05753.x","volume":"65","author":"P Hunt","year":"2007","unstructured":"Hunt, P. et al. Gene encoding a deubiquitinating enzyme is mutated in artesunate- and chloroquine-resistant rodent malaria parasites. Mol. Microbiol. 65, 27\u201340 (2007).","journal-title":"Mol. Microbiol."},{"key":"46006_CR13","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-11-499","volume":"11","author":"P Hunt","year":"2010","unstructured":"Hunt, P. et al. Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites. BMC Genom. 11, 499 (2010).","journal-title":"BMC Genom."},{"key":"46006_CR14","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-12-118","volume":"12","author":"G Henriques","year":"2013","unstructured":"Henriques, G. et al. Artemisinin resistance in rodent malaria-mutation in the AP2 adaptor \u03bc-chain suggests involvement of endocytosis and membrane protein trafficking. Malar. J. 12, 118 (2013).","journal-title":"Malar. J."},{"key":"46006_CR15","doi-asserted-by":"publisher","first-page":"e01542","DOI":"10.1128\/AAC.01542-19","volume":"64","author":"RC Henrici","year":"2019","unstructured":"Henrici, R. C., van Schalkwyk, D. A. & Sutherland, C. J. Modification of pfap2\u03bc and pfubp1 markedly reduces ring-stage susceptibility of Plasmodium falciparum to Artemisinin In Vitro. Antimicrob. Agents Chemother. 64, e01542\u201319 (2019).","journal-title":"Antimicrob. Agents Chemother."},{"key":"46006_CR16","doi-asserted-by":"publisher","first-page":"e02484","DOI":"10.1128\/AAC.02484-19","volume":"64","author":"NV Simwela","year":"2020","unstructured":"Simwela, N. V. et al. Experimentally engineered mutations in a ubiquitin hydrolase, UBP-1, modulate in vivo susceptibility to artemisinin and chloroquine in Plasmodium berghei. Antimicrob. Agents Chemother. 64, e02484\u201319 (2020).","journal-title":"Antimicrob. Agents Chemother."},{"key":"46006_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1204-4","volume":"18","author":"GC Cerqueira","year":"2017","unstructured":"Cerqueira, G. C. et al. Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance. Genome Biol. 18, 78 (2017).","journal-title":"Genome Biol."},{"key":"46006_CR18","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1093\/infdis\/jiu358","volume":"210","author":"G Henriques","year":"2014","unstructured":"Henriques, G. et al. Directional selection at the pfmdr1, pfcrt, pfubp1, and pfap2mu loci of Plasmodium falciparum in Kenyan children treated with ACT. J. Infect. Dis. 210, 2001\u20132008 (2014).","journal-title":"J. Infect. Dis."},{"key":"46006_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/srep03318","volume":"3","author":"S Borrmann","year":"2013","unstructured":"Borrmann, S. et al. Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya. Sci. Rep. 3, 3318 (2013).","journal-title":"Sci. Rep."},{"key":"46006_CR20","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1126\/science.aax4735","volume":"367","author":"J Birnbaum","year":"2020","unstructured":"Birnbaum, J. et al. A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites. Science 367, 51\u201359 (2020).","journal-title":"Science"},{"key":"46006_CR21","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1101\/gr.2866205","volume":"15","author":"R Culleton","year":"2005","unstructured":"Culleton, R., Martinelli, A., Hunt, P. & Carter, R. Linkage group selection: rapid gene discovery in malaria parasites. Genome Res. 15, 92\u201397 (2005).","journal-title":"Genome Res."},{"key":"46006_CR22","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1073\/pnas.0405097102","volume":"102","author":"A Martinelli","year":"2005","unstructured":"Martinelli, A. et al. A genetic approach to the de novo identification of targets of strain-specific immunity in malaria parasites. Proc. Natl. Acad. Sci. USA 102, 814\u2013819 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"46006_CR23","first-page":"E374","volume":"108","author":"J Li","year":"2011","unstructured":"Li, J. et al. Linkage maps from multiple genetic crosses and loci linked to growth-related virulent phenotype in Plasmodium yoelii. Proc. Natl. Acad. Sci. USA 108, E374\u2013382 (2011).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"46006_CR24","doi-asserted-by":"publisher","first-page":"e44","DOI":"10.1371\/journal.ppat.0010044","volume":"1","author":"TWA Kooij","year":"2005","unstructured":"Kooij, T. W. A. et al. A Plasmodium whole-genome synteny map: indels and synteny breakpoints as foci for species-specific genes. PLoS Pathog. 1, e44 (2005).","journal-title":"PLoS Pathog."},{"key":"46006_CR25","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.jmb.2008.08.020","volume":"383","author":"AL Lovering","year":"2008","unstructured":"Lovering, A. L., De Castro, L. & Strynadka, N. C. J. Identification of dynamic structural motifs involved in peptidoglycan glycosyltransfer. J. Mol. Biol. 383, 167\u2013177 (2008).","journal-title":"J. Mol. Biol."},{"key":"46006_CR26","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.ccell.2020.12.003","volume":"39","author":"A Boija","year":"2021","unstructured":"Boija, A., Klein, I. A. & Young, R. A. Biomolecular condensates and cancer. Cancer Cell 39, 174\u2013192 (2021).","journal-title":"Cancer Cell"},{"key":"46006_CR27","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1007\/s11427-020-1702-x","volume":"63","author":"H Zhang","year":"2020","unstructured":"Zhang, H. et al. Liquid-liquid phase separation in biology: mechanisms, physiological functions and human diseases. Sci. China Life Sci. 63, 953\u2013985 (2020).","journal-title":"Sci. China Life Sci."},{"key":"46006_CR28","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/s41586-021-03662-5","volume":"595","author":"JH Ahn","year":"2021","unstructured":"Ahn, J. H. et al. Phase separation drives aberrant chromatin looping and cancer development. Nature 595, 591\u2013595 (2021).","journal-title":"Nature"},{"key":"46006_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-021-02455-3","volume":"22","author":"X Liu","year":"2021","unstructured":"Liu, X. et al. Time-dependent effect of 1,6-hexanediol on biomolecular condensates and 3D chromatin organization. Genome Biol. 22, 230 (2021).","journal-title":"Genome Biol."},{"key":"46006_CR30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102198","volume":"298","author":"B Estavoyer","year":"2022","unstructured":"Estavoyer, B. et al. Mechanisms orchestrating the enzymatic activity and cellular functions of deubiquitinases. J. Biol. Chem. 298, 102198 (2022).","journal-title":"J. Biol. Chem."},{"key":"46006_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07510-5","volume":"9","author":"B Liu","year":"2018","unstructured":"Liu, B., Sureda-G\u00f3mez, M., Zhen, Y., Amador, V., & Reverter, D. A quaternary tetramer assembly inhibits the deubiquitinating activity of USP25. Nat. Commun. 9, 4973 (2018).","journal-title":"Nat. Commun."},{"key":"46006_CR32","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/S1097-2765(05)00077-8","volume":"6","author":"DA Fidock","year":"2000","unstructured":"Fidock, D. A. et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6, 861\u2013871 (2000).","journal-title":"Mol. Cell"},{"key":"46006_CR33","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/S0166-6851(02)00275-X","volume":"126","author":"C Birago","year":"2003","unstructured":"Birago, C. et al. A gene-family encoding small exported proteins is conserved across Plasmodium genus. Mol. Biochem. Parasitol. 126, 209\u2013218 (2003).","journal-title":"Mol. Biochem. Parasitol."},{"key":"46006_CR34","doi-asserted-by":"publisher","first-page":"1937","DOI":"10.1242\/jcs.023150","volume":"121","author":"MD Lazarus","year":"2008","unstructured":"Lazarus, M. D., Schneider, T. G. & Taraschi, T. F. A new model for hemoglobin ingestion and transport by the human malaria parasite Plasmodium falciparum. J. Cell Sci. 121, 1937\u20131949 (2008).","journal-title":"J. Cell Sci."},{"key":"46006_CR35","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1128\/EC.00267-14","volume":"14","author":"KJ Milani","year":"2015","unstructured":"Milani, K. J., Schneider, T. G. & Taraschi, T. F. Defining the morphology and mechanism of the hemoglobin transport pathway in Plasmodium falciparum-infected erythrocytes. Eukaryot. Cell 14, 415\u2013426 (2015).","journal-title":"Eukaryot. Cell"},{"key":"46006_CR36","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.chom.2019.06.001","volume":"26","author":"LS Ross","year":"2019","unstructured":"Ross, L. S. & Fidock, D. A. Elucidating mechanisms of drug-resistant Plasmodium falciparum. Cell Host Microbe 26, 35\u201347 (2019).","journal-title":"Cell Host Microbe"},{"key":"46006_CR37","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-015-0791-3","volume":"14","author":"SJ Reiling","year":"2015","unstructured":"Reiling, S. J. & Rohrbach, P. Monitoring PfMDR1 transport in Plasmodium falciparum. Malar. J. 14, 270 (2015).","journal-title":"Malar. J."},{"key":"46006_CR38","doi-asserted-by":"publisher","first-page":"200390","DOI":"10.1098\/rsob.200390","volume":"11","author":"F Aliabadi","year":"2021","unstructured":"Aliabadi, F., Sohrabi, B., Mostafavi, E., Pazoki-Toroudi, H. & Webster, T. J. Ubiquitin-proteasome system and the role of its inhibitors in cancer therapy. Open Biol. 11, 200390 (2021).","journal-title":"Open Biol."},{"key":"46006_CR39","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nrd.2016.211","volume":"16","author":"AC Lai","year":"2017","unstructured":"Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101\u2013114 (2017).","journal-title":"Nat. Rev. Drug Discov."},{"key":"46006_CR40","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41392-020-0107-0","volume":"5","author":"L Deng","year":"2020","unstructured":"Deng, L., Meng, T., Chen, L., Wei, W. & Wang, P. The role of ubiquitination in tumorigenesis and targeted drug discovery. Signal. Transduct. Target Ther. 5, 11 (2020).","journal-title":"Signal. Transduct. Target Ther."},{"key":"46006_CR41","doi-asserted-by":"publisher","first-page":"e2107213118","DOI":"10.1073\/pnas.2107213118","volume":"118","author":"SC Xie","year":"2021","unstructured":"Xie, S. C. et al. Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome. Proc. Natl. Acad. Sci. USA 118, e2107213118 (2021).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"46006_CR42","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nature16936","volume":"530","author":"H Li","year":"2016","unstructured":"Li, H. et al. Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 530, 233\u2013236 (2016).","journal-title":"Nature"},{"key":"46006_CR43","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.pt.2017.05.009","volume":"33","author":"CL Ng","year":"2017","unstructured":"Ng, C. L., Fidock, D. A. & Bogyo, M. Protein degradation systems as antimalarial therapeutic targets. Trends Parasitol. 33, 731\u2013743 (2017).","journal-title":"Trends Parasitol."},{"key":"46006_CR44","doi-asserted-by":"publisher","first-page":"e1002132","DOI":"10.1371\/journal.pbio.1002132","volume":"13","author":"C Dogovski","year":"2015","unstructured":"Dogovski, C. et al. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biol. 13, e1002132 (2015).","journal-title":"PLoS Biol."},{"key":"46006_CR45","doi-asserted-by":"publisher","first-page":"e1004382","DOI":"10.1371\/journal.pgen.1004382","volume":"10","author":"CP Sanchez","year":"2014","unstructured":"Sanchez, C. P. et al. A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. PLoS Genet. 10, e1004382 (2014).","journal-title":"PLoS Genet."},{"key":"46006_CR46","doi-asserted-by":"publisher","first-page":"e0082122","DOI":"10.1128\/aac.00821-22","volume":"67","author":"BK Singh","year":"2023","unstructured":"Singh, B. K. et al. A Plasmodium falciparum RING Finger E3 Ubiquitin Ligase Modifies the Roles of PfMDR1 and PfCRT in parasite drug responses. Antimicrob. Agents Chemother. 67, e0082122 (2023).","journal-title":"Antimicrob. Agents Chemother."},{"key":"46006_CR47","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1038\/s41564-023-01377-z","volume":"8","author":"A Amambua-Ngwa","year":"2023","unstructured":"Amambua-Ngwa, A. et al. Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1. Nat. Microbiol. 8, 1213\u20131226 (2023).","journal-title":"Nat. Microbiol."},{"key":"46006_CR48","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-13-106","volume":"13","author":"KK Modrzynska","year":"2012","unstructured":"Modrzynska, K. K. et al. Quantitative genome re-sequencing defines multiple mutations conferring chloroquine resistance in rodent malaria. BMC Genom. 13, 106 (2012).","journal-title":"BMC Genom."},{"key":"46006_CR49","doi-asserted-by":"publisher","first-page":"e2386","DOI":"10.1371\/journal.pone.0002386","volume":"3","author":"N Ponts","year":"2008","unstructured":"Ponts, N. et al. Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: a potential strategy to interfere with parasite virulence. PLoS One 3, e2386 (2008).","journal-title":"PLoS One"},{"key":"46006_CR50","doi-asserted-by":"publisher","first-page":"985178","DOI":"10.3389\/fcimb.2022.985178","volume":"12","author":"P Kumar","year":"2022","unstructured":"Kumar, P., Kumar, P., Mandal, D. & Velayutham, R. The emerging role of Deubiquitinases (DUBs) in parasites: a foresight review. Front. Cell Infect. Microbiol. 12, 985178 (2022).","journal-title":"Front. Cell Infect. Microbiol."},{"key":"46006_CR51","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1093\/infdis\/jiac365","volume":"226","author":"KJ Wicht","year":"2022","unstructured":"Wicht, K. J., Small-Saunders, J. L., Hagenah, L. M., Mok, S. & Fidock, D. A. Mutant PfCRT can mediate piperaquine resistance in African Plasmodium falciparum with reduced fitness and increased susceptibility to other antimalarials. J. Infect. Dis. 226, 2021\u20132029 (2022).","journal-title":"J. Infect. Dis."},{"key":"46006_CR52","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/S1473-3099(16)30415-7","volume":"17","author":"B Witkowski","year":"2017","unstructured":"Witkowski, B. et al. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. Lancet Infect. Dis. 17, 174\u2013183 (2017).","journal-title":"Lancet Infect. Dis."},{"key":"46006_CR53","doi-asserted-by":"publisher","first-page":"e1008640","DOI":"10.1371\/journal.ppat.1008640","volume":"16","author":"JL Green","year":"2020","unstructured":"Green, J. L. et al. Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development. PLoS Pathog. 16, e1008640 (2020).","journal-title":"PLoS Pathog."},{"key":"46006_CR54","doi-asserted-by":"publisher","first-page":"40320","DOI":"10.1074\/jbc.M111.238790","volume":"286","author":"N Ponts","year":"2011","unstructured":"Ponts, N. et al. Unraveling the ubiquitome of the human malaria parasite. J. Biol. Chem. 286, 40320\u201340330 (2011).","journal-title":"J. Biol. Chem."},{"key":"46006_CR55","doi-asserted-by":"publisher","unstructured":"van Schalkwyk, D. A. et al. Treatment failure in a UK malaria patient harbouring genetically variant Plasmodium falciparum from Uganda with reduced in vitro susceptibility to artemisinin and lumefantrine. Clin. Infect. Dis. In press, ciad724, https:\/\/doi.org\/10.1093\/cid\/ciad724 (2023).","DOI":"10.1093\/cid\/ciad724"},{"key":"46006_CR56","doi-asserted-by":"publisher","first-page":"e1011814","DOI":"10.1371\/journal.ppat.1011814","volume":"19","author":"S Schmidt","year":"2023","unstructured":"Schmidt, S. et al. The Kelch13 compartment is a hub of highly divergent vesicle trafficking proteins in malaria parasites. PLoS Pathog. 19, e1011814 (2023).","journal-title":"PLoS Pathog."},{"key":"46006_CR57","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1080\/00034983.1978.11719276","volume":"72","author":"W Peters","year":"1978","unstructured":"Peters, W., Chance, M. L., Lissner, R., Momen, H. & Warhurst, D. C. The chemotherapy of rodent malaria, XXX. The enigmas of the \u2018NS lines\u2019 of P. berghei.Ann. Trop. Med. Parasitol. 72, 23\u201336 (1978).","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"46006_CR58","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1080\/00034983.1995.11812978","volume":"89","author":"W Peters","year":"1995","unstructured":"Peters, W., Robinson, B. L., Mittelholzer, M. L., Crevoisier, C. & St\u00fcrchler, D. The chemotherapy of rodent malaria. LII. Response of Plasmodium yoelii ssp. NS to mefloquine and its enantiomers. Ann. Trop. Med. Parasitol. 89, 465\u2013468 (1995).","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"46006_CR59","doi-asserted-by":"crossref","unstructured":"Pattaradilokrat, S., Li, J. & Su, X.-Z. Protocol for Production of a Genetic Cross of the Rodent Malaria Parasites. J. Vis. Exp. 47, 2365 (2011).","DOI":"10.3791\/2365-v"},{"key":"46006_CR60","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.exppara.2012.10.011","volume":"133","author":"Y Qi","year":"2013","unstructured":"Qi, Y. et al. Optimized protocols for improving the likelihood of cloning recombinant progeny from Plasmodium yoelii genetic crosses. Exp. Parasitol. 133, 44\u201350 (2013).","journal-title":"Exp. Parasitol."},{"key":"46006_CR61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.molbiopara.2016.12.010","volume":"212","author":"C Zhang","year":"2017","unstructured":"Zhang, C. et al. CRISPR\/Cas9 mediated sequential editing of genes critical for ookinete motility in Plasmodium yoelii. Mol. Biochem. Parasitol. 212, 1\u20138 (2017).","journal-title":"Mol. Biochem. Parasitol."},{"key":"46006_CR62","doi-asserted-by":"publisher","first-page":"e01414","DOI":"10.1128\/mBio.01414-14","volume":"5","author":"C Zhang","year":"2014","unstructured":"Zhang, C. et al. Efficient editing of malaria parasite genome using the CRISPR\/Cas9 system. mBio 5, e01414\u201314 (2014).","journal-title":"mBio"},{"key":"46006_CR63","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1038\/nbt.2375","volume":"30","author":"JD Martell","year":"2012","unstructured":"Martell, J. D. et al. Engineered ascorbate peroxidase as a genetically encoded reporter for electron microscopy. Nat. Biotechnol. 30, 1143\u20131148 (2012).","journal-title":"Nat. Biotechnol."},{"key":"46006_CR64","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1038\/nprot.2017.065","volume":"12","author":"JD Martell","year":"2017","unstructured":"Martell, J. D., Deerinck, T. J., Lam, S. S., Ellisman, M. H. & Ting, A. Y. Electron microscopy using the genetically encoded APEX2 tag in cultured mammalian cells. Nat. Protoc. 12, 1792\u20131816 (2017).","journal-title":"Nat. Protoc."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-46006-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-46006-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-46006-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,27]],"date-time":"2024-02-27T16:09:44Z","timestamp":1709050184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-46006-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,27]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["46006"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-46006-3","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,27]]},"assertion":[{"value":"20 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1774"}}