Targeted disruption of cytosolic SIR2 deacetylase discloses its essential role in Leishmania survival and proliferation

• Type: Article in International Scientific Journal
• Date: 2005

Authors

Vergnes, B (Author) Other; Sereno, D (Author) Other; Tavares, J (Author) FFUP; Cordeiro da Silva, A (Author) FFUP; Vanhille, L (Author) Other; Madjidian Sereno, N (Author) Other; Depoix, D (Author) Other; Monte Alegre, A (Author) Other; Ouaissi, A (Author) Other

Journal

Title: Gene

Vol. 363

Pages: 85-96

ISSN: 0378-1119

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 54 Citations

Scopus - 58 Citations

Scientific classification

FOS: Natural sciences > Earth and related Environmental sciences

Other information

Authenticus ID: P-000-00T

DOI: 10.1016/j.gene.2005.06.047

Abstract (EN): Proteins of the SIR2 family are characterized by a conserved catalytic domain that exerts unique NAD-dependent deacetylase activity on histone and various other cellular substrates. Functional analyses of such proteins have been carried out in a number of prokaryotes and eukaryotes organisms but until now, none have described an essential function for any SIR2 genes. Here using genetic approach, we report that a cytosolic SIR2 homolog in Leishmania is determinant to parasite survival. L. infantum promastigote tolerates deletion of one wild-type LiSIR2 allele (LiSIR2+/-) but achievement of null chromosomal mutants (LiSIR2-/-) requires episomal rescue. Accordingly, plasmid cure shows that these parasites maintain episome even in absence of drug pressure. Though single LiSIR2 gene disruption (LiSIR2+/-) does not affect the growth of parasite in the promastigote form, axenic amastigotes display a marked reduction in their capacity to multiply in vitro inside macrophages and in vivo in Balb/c mice. Taken together these data support a stage specific requirement and/or activity of the Leishmania cytosolic SIR2 protein and reveal an unrelated essential function for the life cycle of this unicellular pathogenic organism. The lack of an effective vaccine against leishmaniasis, and the need for alternative drug treatments, makes LiSIR2 protein a new attractive therapeutic target.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12