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N-acetylglucosamine supplementation fails to bypass the critical acetylation of glucosamine-6-phosphate required for Toxoplasma gondii replication and invasion.
Alberione, María Pía; González-Ruiz, Víctor; von Rohr, Olivier; Rudaz, Serge; Soldati-Favre, Dominique; Izquierdo, Luis; Kloehn, Joachim.
Afiliación
  • Alberione MP; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, Barcelona, Spain.
  • González-Ruiz V; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
  • von Rohr O; Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
  • Rudaz S; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
  • Soldati-Favre D; Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland.
  • Izquierdo L; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, Barcelona, Spain.
  • Kloehn J; CIBER de Enfermedades Infecciosas (CIBERINFEC), Barcelona, Spain.
PLoS Pathog ; 20(6): e1011979, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38900808
ABSTRACT
The cell surface of Toxoplasma gondii is rich in glycoconjugates which hold diverse and vital functions in the lytic cycle of this obligate intracellular parasite. Additionally, the cyst wall of bradyzoites, that shields the persistent form responsible for chronic infection from the immune system, is heavily glycosylated. Formation of glycoconjugates relies on activated sugar nucleotides, such as uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). The glucosamine-phosphate-N-acetyltransferase (GNA1) generates N-acetylglucosamine-6-phosphate critical to produce UDP-GlcNAc. Here, we demonstrate that downregulation of T. gondii GNA1 results in a severe reduction of UDP-GlcNAc and a concomitant drop in glycosylphosphatidylinositols (GPIs), leading to impairment of the parasite's ability to invade and replicate in the host cell. Surprisingly, attempts to rescue this defect through exogenous GlcNAc supplementation fail to completely restore these vital functions. In depth metabolomic analyses elucidate diverse causes underlying the failed rescue utilization of GlcNAc is inefficient under glucose-replete conditions and fails to restore UDP-GlcNAc levels in GNA1-depleted parasites. In contrast, GlcNAc-supplementation under glucose-deplete conditions fully restores UDP-GlcNAc levels but fails to rescue the defects associated with GNA1 depletion. Our results underscore the importance of glucosamine-6-phosphate acetylation in governing T. gondii replication and invasion and highlight the potential of the evolutionary divergent GNA1 in Apicomplexa as a target for the development of much-needed new therapeutic strategies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Acetilglucosamina / Toxoplasma / Glucosa-6-Fosfato Límite: Animals / Humans Idioma: En Revista: PLoS Pathog Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Acetilglucosamina / Toxoplasma / Glucosa-6-Fosfato Límite: Animals / Humans Idioma: En Revista: PLoS Pathog Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos