<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2XII-2 Contributes to Proper Progression through S-Phase of the Cell Cycle

ABSTRACT Toxoplasma gondii is a protozoan parasite that causes lifelong chronic infection that can reactivate in immunocompromised individuals. Upon infection, the replicative stage (tachyzoite) converts into a latent tissue cyst stage (bradyzoite). Like other apicomplexans, T. gondii possesses an e...

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Autores principales: Sandeep Srivastava, Michael W. White, William J. Sullivan
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Publicado: American Society for Microbiology 2020
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spelling oai:doaj.org-article:9961327865f94baebdeec62bcfc854612021-11-15T15:30:58Z<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2XII-2 Contributes to Proper Progression through S-Phase of the Cell Cycle10.1128/mSphere.00542-202379-5042https://doaj.org/article/9961327865f94baebdeec62bcfc854612020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00542-20https://doaj.org/toc/2379-5042ABSTRACT Toxoplasma gondii is a protozoan parasite that causes lifelong chronic infection that can reactivate in immunocompromised individuals. Upon infection, the replicative stage (tachyzoite) converts into a latent tissue cyst stage (bradyzoite). Like other apicomplexans, T. gondii possesses an extensive lineage of proteins called ApiAP2s that contain DNA-binding domains first characterized in plants. The function of most ApiAP2s is unknown. We previously found that AP2IX-4 is a cell cycle-regulated ApiAP2 expressed only in dividing parasites as a putative transcriptional repressor. In this study, we purified proteins interacting with AP2IX-4, finding it to be a component of the recently characterized microrchidia (MORC) transcriptional repressor complex. We further analyzed AP2XII-2, another cell cycle-regulated factor that associates with AP2IX-4. We monitored parallel expression of AP2IX-4 and AP2XII-2 proteins in tachyzoites, detecting peak expression during S/M phase. Unlike AP2IX-4, which is dispensable in tachyzoites, loss of AP2XII-2 resulted in a slowed tachyzoite growth due to a delay in S-phase progression. We also found that AP2XII-2 depletion increased the frequency of bradyzoite differentiation in vitro. These results suggest that multiple AP2 factors collaborate to ensure proper cell cycle progression and tissue cyst formation in T. gondii. IMPORTANCE Toxoplasma gondii is a single-celled parasite that persists in its host by converting into a latent cyst stage. This work describes a new transcriptional factor called AP2XII-2 that plays a role in properly maintaining the growth rate of replicating parasites, which contributes to signals required for development into its dormant stage. Without AP2XII-2, Toxoplasma parasites experience a delay in their cell cycle that increases the frequency of latent cyst formation. In addition, we found that AP2XII-2 operates in a multisubunit complex with other AP2 factors and chromatin remodeling machinery that represses gene expression. These findings add to our understanding of how Toxoplasma parasites balance replication and dormancy, revealing novel points of potential therapeutic intervention to disrupt this clinically relevant process.Sandeep SrivastavaMichael W. WhiteWilliam J. SullivanAmerican Society for MicrobiologyarticleApicomplexaToxoplasmacell cyclechromatindifferentiationparasitesMicrobiologyQR1-502ENmSphere, Vol 5, Iss 5 (2020)
institution DOAJ
collection DOAJ
language EN
topic Apicomplexa
Toxoplasma
cell cycle
chromatin
differentiation
parasites
Microbiology
QR1-502
spellingShingle Apicomplexa
Toxoplasma
cell cycle
chromatin
differentiation
parasites
Microbiology
QR1-502
Sandeep Srivastava
Michael W. White
William J. Sullivan
<named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2XII-2 Contributes to Proper Progression through S-Phase of the Cell Cycle
description ABSTRACT Toxoplasma gondii is a protozoan parasite that causes lifelong chronic infection that can reactivate in immunocompromised individuals. Upon infection, the replicative stage (tachyzoite) converts into a latent tissue cyst stage (bradyzoite). Like other apicomplexans, T. gondii possesses an extensive lineage of proteins called ApiAP2s that contain DNA-binding domains first characterized in plants. The function of most ApiAP2s is unknown. We previously found that AP2IX-4 is a cell cycle-regulated ApiAP2 expressed only in dividing parasites as a putative transcriptional repressor. In this study, we purified proteins interacting with AP2IX-4, finding it to be a component of the recently characterized microrchidia (MORC) transcriptional repressor complex. We further analyzed AP2XII-2, another cell cycle-regulated factor that associates with AP2IX-4. We monitored parallel expression of AP2IX-4 and AP2XII-2 proteins in tachyzoites, detecting peak expression during S/M phase. Unlike AP2IX-4, which is dispensable in tachyzoites, loss of AP2XII-2 resulted in a slowed tachyzoite growth due to a delay in S-phase progression. We also found that AP2XII-2 depletion increased the frequency of bradyzoite differentiation in vitro. These results suggest that multiple AP2 factors collaborate to ensure proper cell cycle progression and tissue cyst formation in T. gondii. IMPORTANCE Toxoplasma gondii is a single-celled parasite that persists in its host by converting into a latent cyst stage. This work describes a new transcriptional factor called AP2XII-2 that plays a role in properly maintaining the growth rate of replicating parasites, which contributes to signals required for development into its dormant stage. Without AP2XII-2, Toxoplasma parasites experience a delay in their cell cycle that increases the frequency of latent cyst formation. In addition, we found that AP2XII-2 operates in a multisubunit complex with other AP2 factors and chromatin remodeling machinery that represses gene expression. These findings add to our understanding of how Toxoplasma parasites balance replication and dormancy, revealing novel points of potential therapeutic intervention to disrupt this clinically relevant process.
format article
author Sandeep Srivastava
Michael W. White
William J. Sullivan
author_facet Sandeep Srivastava
Michael W. White
William J. Sullivan
author_sort Sandeep Srivastava
title <named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2XII-2 Contributes to Proper Progression through S-Phase of the Cell Cycle
title_short <named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2XII-2 Contributes to Proper Progression through S-Phase of the Cell Cycle
title_full <named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2XII-2 Contributes to Proper Progression through S-Phase of the Cell Cycle
title_fullStr <named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2XII-2 Contributes to Proper Progression through S-Phase of the Cell Cycle
title_full_unstemmed <named-content content-type="genus-species">Toxoplasma gondii</named-content> AP2XII-2 Contributes to Proper Progression through S-Phase of the Cell Cycle
title_sort <named-content content-type="genus-species">toxoplasma gondii</named-content> ap2xii-2 contributes to proper progression through s-phase of the cell cycle
publisher American Society for Microbiology
publishDate 2020
url https://doaj.org/article/9961327865f94baebdeec62bcfc85461
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