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Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells

2020Journal article Open access
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dc.contributor.authorSetua, Sonali
dc.contributor.authorEnguita, Francisco J.
dc.contributor.authorChora, Ângelo Ferreira
dc.contributor.authorRanga-prasad, Harish
dc.contributor.authorLahree, Aparajita
dc.contributor.authorMarques, Sofia
dc.contributor.authorSundaramurthy, Varadharajan
dc.contributor.authorMota, Maria M.
dc.date.accessioned2021-04-06T17:18:42Z
dc.date.available2021-04-06T17:18:42Z
dc.date.issued2020
dc.description© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.pt_PT
dc.description.abstractThe malaria parasite Plasmodium obligatorily infects and replicates inside hepatocytes surrounded by a parasitophorous vacuole membrane (PVM), which is decorated by the host-cell derived autophagy protein LC3. We have previously shown that the parasite-derived, PVM-resident protein UIS3 sequesters LC3 to avoid parasite elimination by autophagy from hepatocytes. Here we show that a small molecule capable of disrupting this interaction triggers parasite elimination in a host cell autophagy-dependent manner. Molecular docking analysis of more than 20 million compounds combined with a phenotypic screen identified one molecule, C4 (4-{[4-(4-{5-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazol-3-yl}benzyl)piperazino]carbonyl}benzonitrile), capable of impairing infection. Using biophysical assays, we established that this impairment is due to the ability of C4 to disrupt UIS3–LC3 interaction, thus inhibiting the parasite’s ability to evade the host autophagy response. C4 impacts infection in autophagy-sufficient cells without harming the normal autophagy pathway of the host cell. This study, by revealing the disruption of a critical host–parasite interaction without affecting the host’s normal function, uncovers an efficient anti-malarial strategy to prevent this deadly disease.pt_PT
dc.description.sponsorshipThis work was supported by grants from Institut Mérieux (MRG_20052016 to M.M.M). S.S. and A.F.C. were recipients of Fundação para a Ciência e Tecnologia fellowships SFRH/BPD/116451/2016 and SFRH/BPD/112009/2015, respectively. H.R. and V.S. were supported by core funds from NCBS-TIFR. A.L. was supported by Sanofi-Institut Pasteur 2018 Prize to M.M.M.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCommun Biol. 2020 Nov 19;3(1):688pt_PT
dc.identifier.doi10.1038/s42003-020-01422-1pt_PT
dc.identifier.eissn2399-3642
dc.identifier.urihttp://hdl.handle.net/10451/47262
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationUnveiling the key host-pathogen interactions during asymptomatic liver-stage of malaria
dc.relationMolecular and celullar mechanisms of Plasmodium sensing during malarial liver-stage infection
dc.relation.publisherversionhttps://www.nature.com/commsbio/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleDisrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleUnveiling the key host-pathogen interactions during asymptomatic liver-stage of malaria
oaire.awardTitleMolecular and celullar mechanisms of Plasmodium sensing during malarial liver-stage infection
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBPD%2F116451%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBPD%2F112009%2F2015/PT
oaire.citation.issue1pt_PT
oaire.citation.titleCommunications Biologypt_PT
oaire.citation.volume3pt_PT
oaire.fundingStreamOE
oaire.fundingStreamOE
person.familyNameSetua
person.familyNameEnguita
person.familyNameFerreira Chaves do Rosário Chora
person.familyNameLahree
person.familyNameMarques
person.familyNameMota
person.givenNameSonali
person.givenNameFrancisco J.
person.givenNameÂngelo António
person.givenNameAparajita
person.givenNameSofia
person.givenNameMaria Manuel
person.identifier173306
person.identifier.ciencia-idB215-8D49-3218
person.identifier.ciencia-id8112-E177-A53D
person.identifier.ciencia-id3416-653D-20B9
person.identifier.ciencia-id201E-7D43-52AA
person.identifier.ciencia-id4217-0969-297E
person.identifier.orcid0000-0002-6673-5240
person.identifier.orcid0000-0002-8072-8557
person.identifier.orcid0000-0002-7941-7196
person.identifier.orcid0000-0002-2341-7269
person.identifier.orcid0000-0003-1467-1529
person.identifier.orcid0000-0002-2858-1041
person.identifier.ridA-2347-2009
person.identifier.scopus-author-id6602119231
person.identifier.scopus-author-id7004641665
person.identifier.scopus-author-id7102709816
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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