3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication

Yubao Wang, Anuradha Karnataki, Marilyn Parsons, Louis M. Weiss, Amos Orlofsky

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The apicomplexan Toxoplasma gondii replicates by endodyogeny, in which replicated organelles assemble into nascent daughter buds within the maternal parasite. The mechanisms governing this complex sequence are not understood. We now report that the kinase inhibitor 3-methlyadenine (3-MA) efficiently blocks T. gondii replication. The inhibition could not be attributed to the effects of 3-MA on mammalian phosphatidylinositol 3-kinase and host cell autophagy. Furthermore, we show that accumulation of host lysosomes around the parasitophorous vacuoles was unaffected. Most 3-MA-treated parasites failed to form daughter buds or replicate DNA, indicating arrest in G1 or early S-phase. Some 3-MA-treated parasites displayed abortive cell division, in which nuclear segregation to malformed daughter buds was incomplete or asymmetrical. Electron microscopy revealed the presence of residual body-like structures in many vacuoles, even in the absence of daughter buds. Most treated parasites had otherwise normal morphology and were able to resume replication upon drug removal. 3-MA-treated and control parasites were similar with respect to the extent of Golgi body division and apicoplast elongation; however, treated parasites rarely possessed replicated centrosomes or apicoplasts. These data are suggestive of a generalized blockade of T. gondii cell cycle progression at stages preceding centrosome replication, rather than arrest at a specific checkpoint. We hypothesize that 3-MA treatment triggers a cell cycle pause program that may serve to protect parasites during periods, such as subsequent to egress, when cell cycle progression might be deleterious. Elucidation of the mechanism of 3-MA inhibition may provide insight into the control of parasite growth.

Original languageEnglish (US)
Pages (from-to)142-153
Number of pages12
JournalMolecular and Biochemical Parasitology
Volume173
Issue number2
DOIs
StatePublished - Oct 2010

Fingerprint

Centrosome
Toxoplasma
Parasites
Apicoplasts
Communicable Disease Control
Cell Cycle
Vacuoles
Phosphatidylinositol 3-Kinase
Autophagy
Lysosomes
S Phase
Organelles
Cell Division
3-methyladenine
Electron Microscopy
Phosphotransferases
Mothers
DNA
Growth
Pharmaceutical Preparations

Keywords

  • 3-Methyladenine
  • Apicoplast
  • Cell cycle
  • Centrosome
  • Endodyogeny
  • Toxoplasma

ASJC Scopus subject areas

  • Molecular Biology
  • Parasitology
  • Medicine(all)

Cite this

3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication. / Wang, Yubao; Karnataki, Anuradha; Parsons, Marilyn; Weiss, Louis M.; Orlofsky, Amos.

In: Molecular and Biochemical Parasitology, Vol. 173, No. 2, 10.2010, p. 142-153.

Research output: Contribution to journalArticle

Wang, Yubao ; Karnataki, Anuradha ; Parsons, Marilyn ; Weiss, Louis M. ; Orlofsky, Amos. / 3-Methyladenine blocks Toxoplasma gondii division prior to centrosome replication. In: Molecular and Biochemical Parasitology. 2010 ; Vol. 173, No. 2. pp. 142-153.
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