TgAP2IX-5 is a key transcriptional regulator of the asexual cell cycle division in Toxoplasma gondii

Asma S Khelifa,Emmanuel Roger,Ludovic Huot,Cecilia Guillen Sanchez,Thomas Mouveaux,Guillemette Marot,Kevin M Lesage,Helene Touzet,Mathieu Gissot,Nicolas Barois,Pierre Pericard

doi:10.1038/s41467-020-20216-x

Abstract

Apicomplexan parasites have evolved efficient and distinctive strategies for intracellular replication where the timing of emergence of the daughter cells (budding) is a decisive element. However, the molecular mechanisms that provide the proper timing of parasite budding remain unknown. Using Toxoplasma gondii as a model Apicomplexan, we identified a master regulator that controls the timing of the budding process. We show that an ApiAP2 transcription factor, TgAP2IX-5, controls cell cycle events downstream of centrosome duplication. TgAP2IX-5 binds to the promoter of hundreds of genes and controls the activation of the budding-specific cell cycle expression program. TgAP2IX-5 regulates the expression of specific transcription factors that are necessary for the completion of the budding cycle. Moreover, TgAP2IX-5 acts as a limiting factor that ensures that asexual proliferation continues by promoting the inhibition of the differentiation pathway. Therefore, TgAP2IX-5 is a master regulator that controls both cell cycle and developmental pathways.

Highlights

Apicomplexan parasites have evolved efficient and distinctive strategies for intracellular replication where the timing of emergence of the daughter cells is a decisive element
We focused on the ApiAP2 family of transcription factors and discovered that the tgap2ix-5 transcript was dynamically expressed with a peak of expression within the S phase
To confirm that the TgAP2IX-5 protein was cell cycle regulated, we produced a T. gondii strain that had an epitopetagged version of this gene at its endogenous locus

Summary

Introduction

Apicomplexan parasites have evolved efficient and distinctive strategies for intracellular replication where the timing of emergence of the daughter cells (budding) is a decisive element. In addition to endodyogeny, which is the simplest form of internal budding, T. gondii asexually divides within its definitive host through a division scheme that closely resembles schizogony and is known as endopolygeny It consists of the production of multiple nuclei and a final step of daughter cell formation where parasites perform internal budding in the cytoplasm, unlike schizogony[7]. These distinct replication patterns (endodyogeny, schizogony, and endopolygeny) rely on the coordination of the timing of the budding and nuclear cycles Apicomplexa, such as T. gondii, which exhibit endodyogeny and endopolygeny, are able to employ several division patterns depending on the cellular microenvironment and the developmental stage of the parasite’s lifecycle. Evidence suggests that soon after centrosome division, centrosome maturation through kinases is key to the activation of daughter cell formation[10,11]

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Conclusion