Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/47262 |
Resumo: | © 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/. |
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Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells© 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/.The 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.This 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.Springer NatureRepositório da Universidade de LisboaSetua, SonaliEnguita, Francisco J.Chora, Ângelo FerreiraRanga-prasad, HarishLahree, AparajitaMarques, SofiaSundaramurthy, VaradharajanMota, Maria M.2021-04-06T17:18:42Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/47262engCommun Biol. 2020 Nov 19;3(1):68810.1038/s42003-020-01422-12399-3642info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:50:04Zoai:repositorio.ul.pt:10451/47262Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:59:20.683896Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells |
title |
Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells |
spellingShingle |
Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells Setua, Sonali |
title_short |
Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells |
title_full |
Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells |
title_fullStr |
Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells |
title_full_unstemmed |
Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells |
title_sort |
Disrupting Plasmodium UIS3–host LC3 interaction with a small molecule causes parasite elimination from host cells |
author |
Setua, Sonali |
author_facet |
Setua, Sonali Enguita, Francisco J. Chora, Ângelo Ferreira Ranga-prasad, Harish Lahree, Aparajita Marques, Sofia Sundaramurthy, Varadharajan Mota, Maria M. |
author_role |
author |
author2 |
Enguita, Francisco J. Chora, Ângelo Ferreira Ranga-prasad, Harish Lahree, Aparajita Marques, Sofia Sundaramurthy, Varadharajan Mota, Maria M. |
author2_role |
author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Setua, Sonali Enguita, Francisco J. Chora, Ângelo Ferreira Ranga-prasad, Harish Lahree, Aparajita Marques, Sofia Sundaramurthy, Varadharajan Mota, Maria M. |
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/. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z 2021-04-06T17:18:42Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/47262 |
url |
http://hdl.handle.net/10451/47262 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Commun Biol. 2020 Nov 19;3(1):688 10.1038/s42003-020-01422-1 2399-3642 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
Springer Nature |
publisher.none.fl_str_mv |
Springer Nature |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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