Leishmania encodes a bacterium-like 2,4-dienoyl-coenzyme a reductase that is required for fatty acid β-oxidation and intracellular parasite survival

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Autor(es): dc.contributorRobert Koch Institute-
Autor(es): dc.contributorThe University of Edinburgh-
Autor(es): dc.contributorUniversity of Glasgow-
Autor(es): dc.contributorUniversity of Melbourne-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorLeibniz-Institute for Molecular Pharmacology-
Autor(es): dc.creatorSemini, Geo-
Autor(es): dc.creatorPaape, Daniel-
Autor(es): dc.creatorBlume, Martin-
Autor(es): dc.creatorFleur Sernee, M.-
Autor(es): dc.creatorPeres-Alonso, Diego [UNESP]-
Autor(es): dc.creatorCalvignac-Spencer, Sébastien-
Autor(es): dc.creatorDöllinger, Jörg-
Autor(es): dc.creatorJehle, Stefan-
Autor(es): dc.creatorSaunders, Eleanor-
Autor(es): dc.creatorMcConville, Malcolm J.-
Autor(es): dc.creatorAebischer, Toni-
Data de aceite: dc.date.accessioned2022-08-04T22:08:42Z-
Data de disponibilização: dc.date.available2022-08-04T22:08:42Z-
Data de envio: dc.date.issued2022-04-28-
Data de envio: dc.date.issued2022-04-28-
Data de envio: dc.date.issued2020-05-01-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1128/mBio.01057-20-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/221490-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/221490-
Descrição: dc.descriptionLeishmania spp. are protozoan parasites that cause a spectrum of important diseases in humans. These parasites develop as extracellular promastigotes in the digestive tract of their insect vectors and as obligate intracellular amastigotes that infect macrophages and other phagocytic cells in their vertebrate hosts. Promastigote-to-amastigote differentiation is associated with marked changes in me-tabolism, including the upregulation of enzymes involved in fatty acid β-oxidation, which may reflect adaptation to the intracellular niche. Here, we have investigated the function of one of these enzymes, a putative 2,4-dienoyl-coenzyme A (CoA) re-ductase (DECR), which is specifically required for the β-oxidation of polyunsaturated fatty acids. The Leishmania DECR shows close homology to bacterial DECR proteins, suggesting that it was acquired by lateral gene transfer. It is present in other trypanosomatids that have obligate intracellular stages (i.e., Trypanosoma cruzi and Angomonas) but is absent from dixenous parasites with an exclusively extracellular lifestyle (i.e., Trypanosoma brucei). A DECR-green fluorescent protein (GFP) fusion protein was localized to the mitochondrion in both promastigote and amastigote stages, and the levels of expression increased in the latter stages. A Leishmania major Δdecr null mutant was unable to catabolize unsaturated fatty acids and accumu-lated the intermediate 2,4-decadienoyl-CoA, confirming DECR’s role in β-oxidation. Strikingly, the L. major Δdecr mutant was unable to survive in macrophages and was avirulent in BALB/c mice. These findings suggest that β-oxidation of polyunsaturated fatty acids is essential for intracellular parasite survival and that the bacterial origin of key enzymes in this pathway could be exploited in developing new therapies. IMPORTANCE The Trypanosomatidae are protozoan parasites that infect insects, plants, and animals and have evolved complex monoxenous (single host) and dix-enous (two hosts) lifestyles. A number of species of Trypanosomatidae, including Leishmania spp., have evolved the capacity to survive within intracellular niches in vertebrate hosts. The adaptations, metabolic and other, that are associated with development of intracellular lifestyles remain poorly defined. We show that genomes of Leishmania and Trypanosomatidae that can survive intracellularly encode a 2,4-dienoyl-CoA reductase that is involved in catabolism of a subclass of fatty acids. The trypanosomatid enzyme shows closest similarity to the corresponding bacterial enzymes and is located in the mitochondrion and essential for intracellular growth of Leishmania. The findings suggest that acquisition of this gene by lateral gene transfer from bacteria by ancestral monoxenous Trypanosomatidae likely contributed to the development of a dixenous lifestyle of these parasites.-
Descrição: dc.descriptionNational Health and Medical Research Council-
Descrição: dc.descriptionBundesministerium für Bildung und Forschung-
Descrição: dc.descriptionMycotic and Parasitic Agents and Mycobacteria (FG16) Department of Infectious Diseases Robert Koch Institute-
Descrição: dc.descriptionInstitute of Immunology and Infection Research The University of Edinburgh-
Descrição: dc.descriptionWellcome Centre for Integrative Parasitology University of Glasgow-
Descrição: dc.descriptionMetabolism of Microbial Pathogens (NG2) Robert Koch Institute-
Descrição: dc.descriptionDepartment of Biochemistry and Molecular Biology Bio21 Molecular Science and Biotechnology Institute University of Melbourne-
Descrição: dc.descriptionDepartamento de Parasitologia Instituto de Biociências Universidade Estadual Paulista-
Descrição: dc.descriptionEpidemiology of Highly Pathogenic Microorganisms Robert Koch Institute-
Descrição: dc.descriptionProteomics and Spectroscopy (ZBS 6) Robert Koch Institute-
Descrição: dc.descriptionDepartment of NMR-supported Structural Biology Leibniz-Institute for Molecular Pharmacology-
Descrição: dc.descriptionDepartamento de Parasitologia Instituto de Biociências Universidade Estadual Paulista-
Descrição: dc.descriptionBundesministerium für Bildung und Forschung: 01KI1715-
Idioma: dc.languageen-
Relação: dc.relationmBio-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectKinetoplastida-
Palavras-chave: dc.subjectLateral gene transfer-
Palavras-chave: dc.subjectMitochondrial metabolism-
Palavras-chave: dc.subjectVirulence factors-
Título: dc.titleLeishmania encodes a bacterium-like 2,4-dienoyl-coenzyme a reductase that is required for fatty acid β-oxidation and intracellular parasite survival-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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