4.7 Article

The beta subunit of AMP-activated protein kinase is critical for cell cycle progression and parasite development in Toxoplasma gondii

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出版社

SPRINGER BASEL AG
DOI: 10.1007/s00018-022-04556-z

关键词

Toxoplasma gondii; AMPK; Cell cycle; Phosphorylation; Bradyzoite development

资金

  1. Guangdong Major Project of Basic and Applied Basic Research [2020B0301030007]
  2. National Natural Science Foundation of China [31822054]

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The study revealed that AMPK plays crucial roles in controlling cell cycle progression and bradyzoite development in Toxoplasma. Deletion of the beta subunit of AMPK resulted in DNA damage and increased conversion to bradyzoites. Under alkaline stress, AMPK beta mutants transitioned to a bradyzoite-like state but with impaired cell division pattern and compromised parasite viability.
Toxoplasma gondii is a widespread eukaryotic pathogen that causes life-threatening diseases in humans and diverse animals. It has a complex life cycle with multiple developmental stages, which are timely adjusted according to growth conditions. But the regulatory mechanisms are largely unknown. Here we show that the AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis in eukaryotes, plays crucial roles in controlling the cell cycle progression and bradyzoite development in Toxoplasma. Deleting the beta regulatory subunit of AMPK in the type II strain ME49 caused massive DNA damage and increased spontaneous conversion to bradyzoites (parasites at chronic infection stage), leading to severe growth arrest and reduced virulence of the parasites. Under alkaline stress, all Delta ampk beta mutants converted to a bradyzoite-like state but the cell division pattern was significantly impaired, resulting in compromised parasite viability. Moreover, we found that phosphorylation of the catalytic subunit AMPK alpha was greatly increased in alkaline stressed parasites, whereas AMPK beta deletion mutants failed to do so. Phosphoproteomics found that many proteins with predicted roles in cell cycle and cell division regulation were differentially phosphorylated after AMPK beta deletion, under both normal and alkaline stress conditions. Together, these results suggest that the parasite AMPK has critical roles in safeguarding cell cycle progression, and guiding the proper exist of the cell cycle to form mature bradyzoites when the parasites are stressed. Consistent with this model, growth of parasites was not significantly altered when AMPK beta was deleted in a strain that was naturally reluctant to bradyzoite development.

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