Leishmania Mitochondrial Peroxiredoxin Plays a Crucial Peroxidase-Unrelated Role during Infection: Insight into Its Novel Chaperone Activity

• Tipo: Artigo em Revista Científica Internacional
• Data: 2011

Autores

Helena Castro (Autor) Outra; Filipa Teixeira (Autor) Outra; Susana Romao (Autor) Outra; Mariana Santos (Autor) Outra; Tania Cruz (Autor) Outra; Manuela Florido (Autor) Outra; Rui Appelberg (Autor) ICBAS; Pedro Oliveira (Autor) ICBAS; Frederico Ferreira da Silva (Autor) Outra; Ana M Tomas (Autor) ICBAS

Revista

Título: PLoS Pathogens

Vol. 7 Nº 10

Página Final: e1002325

ISSN: 1553-7366

Editora: Public Library of Science

Indexação

ISI Web of Knowledge - 54 Citações

Scopus - 70 Citações

Classificação Científica

FOS: Ciências médicas e da saúde > Ciências da saúde

CORDIS: Ciências da Saúde > Ciências Médicas > Medicina > Infecções

Outras Informações

ID Authenticus: P-002-KSF

DOI: 10.1371/journal.ppat.1002325

Abstract (EN): Two-cysteine peroxiredoxins are ubiquitous peroxidases that play various functions in cells. In Leishmania and related trypanosomatids, which lack catalase and selenium-glutathione peroxidases, the discovery of this family of enzymes provided the molecular basis for peroxide removal in these organisms. In this report the functional relevance of one of such enzymes, the mitochondrial 2-Cys peroxiredoxin (mTXNPx), was investigated along the Leishmania infantum life cycle. mTXNPx null mutants (mtxnpx(-)) produced by a gene replacement strategy, while indistinguishable from wild type promastigotes, were found unable to thrive in a murine model of infection. Unexpectedly, however, the avirulent phenotype of mtxnpx(-) was not due to lack of the peroxidase activity of mTXNPx as these behaved like controls when exposed to oxidants added exogenously or generated by macrophages during phagocytosis ex vivo. In line with this, mtxnpx(-) were also avirulent when inoculated into murine hosts unable to mount an effective oxidative phagocyte response (B6.p47(phox-/-) and B6.RAG2(-/-) IFN-gamma(-/-) mice). Definitive conclusion that the peroxidase activity of mTXNPx is not required for parasite survival in mice was obtained by showing that a peroxidase-inactive version of this protein was competent in rescuing the non-infective phenotype of mtxnpx(-). A novel function is thus proposed for mTXNPx, that of a molecular chaperone, which may explain the impaired infectivity of the null mutants. This premise is based on the observation that the enzyme is able to suppress the thermal aggregation of citrate synthase in vitro. Also, mtxnpx- were more sensitive than controls to a temperature shift from 25 degrees C to 37 degrees C, a phenotype reminiscent of organisms lacking specific chaperone genes. Collectively, the findings reported here change the paradigm which regards all trypanosomatid 2-Cys peroxiredoxins as peroxide-eliminating devices. Moreover, they demonstrate, for the first time, that these 2-Cys peroxiredoxins can be determinant for pathogenicity independently of their peroxidase activity.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 11