Protein phosphatase 1 regulates atypical mitotic and meiotic division in Plasmodium sexual stages

Mohammad Zeeshan,Sue Vaughan,Declan Brady,Arnab Pain,Amit Kumar Subudhi,Rajan Pandey,David J P Ferguson,Andrew R Bottrill,Anthony A Holder,Rita Tewari,David S Guttery,Raushan Nugmanova,Gursimran Kaur,Ravish Rashpa,Mathieu Brochet,Mathieu Bollen

doi:10.1038/s42003-021-02273-0

Abstract

PP1 is a conserved eukaryotic serine/threonine phosphatase that regulates many aspects of mitosis and meiosis, often working in concert with other phosphatases, such as CDC14 and CDC25. The proliferative stages of the malaria parasite life cycle include sexual development within the mosquito vector, with male gamete formation characterized by an atypical rapid mitosis, consisting of three rounds of DNA synthesis, successive spindle formation with clustered kinetochores, and a meiotic stage during zygote to ookinete development following fertilization. It is unclear how PP1 is involved in these unusual processes. Using real-time live-cell and ultrastructural imaging, conditional gene knockdown, RNA-seq and proteomic approaches, we show that Plasmodium PP1 is implicated in both mitotic exit and, potentially, establishing cell polarity during zygote development in the mosquito midgut, suggesting that small molecule inhibitors of PP1 should be explored for blocking parasite transmission.

Highlights

PP1 is a conserved eukaryotic serine/threonine phosphatase that regulates many aspects of mitosis and meiosis, often working in concert with other phosphatases, such as CDC14 and CDC25
Previous studies determined that P. falciparum PP1 functionally complements the Saccharomyces cerevisiae glc[7] (PP1) homologue[26], and subsequent phylogenetic analyses revealed that homologues of the phosphatases CDC14 and CDC25 are absent from Plasmodium[23]
Plasmodium possesses a set of divergent protein kinases and protein phosphatases, which regulate many processes during cell division and parasite development throughout different stages of the life-cycle[23,52], and PP1 is quantitatively one of the most important protein phosphatases that hydrolyse serine/threonine linked phosphate ester bonds[53]

Summary

Introduction

PP1 is a conserved eukaryotic serine/threonine phosphatase that regulates many aspects of mitosis and meiosis, often working in concert with other phosphatases, such as CDC14 and CDC25. The proliferative stages of the malaria parasite life cycle include sexual development within the mosquito vector, with male gamete formation characterized by an atypical rapid mitosis, consisting of three rounds of DNA synthesis, successive spindle formation with clustered kinetochores, and a meiotic stage during zygote to ookinete development following fertilization It is unclear how PP1 is involved in these unusual processes. Protein Phosphatase 1 (PP1) is a member of the PPP family and is expressed in all eukaryotic cells It plays a key role in the progression of mitosis through dephosphorylation of a large variety of proteins, including mitotic kinases (such as cyclindependent kinase 1 (CDK1)[8,9,10,11], and regulators of chromosome segregation[12]. Most studies in Plasmodium have been focused on these asexual blood stages of parasite proliferation, and very little is known about the importance of PP1 for transmission stages within the mosquito vector

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Conclusion