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Control of malarial invasion by phosphorylation of the host cell membrane cytoskeleton
Abstract:
It has been shown that the entry of the malaria parasite into the red blood cell requires the presence of ATP in the host cell cytoplasm. In red blood cell ghosts that contain no ATP the receptor on the extracellular surface remains in place and parasites will bind to the membrane, but will not enter. ATP is thus necessary for one of the steps in the invasion sequence that follows recognition and attachment. The process of entry appears to involve the active participation of the host cell membrane cytoskeleton. We have suggested that the function of the intracellular ATP may be to regulate phosphorylation of the cytoskeleton. We now present evidence that the activity of the membrane-associated cyclic AMP-independent kinase of the red blood cell is inseparable from invasion; the active substrate may be spectrin.
Insights
Adenosine triphosphate (ATP) is crucial for malaria parasite invasion into red blood cells, facilitating entry after initial attachment. This energy molecule likely regulates red blood cell cytoskeleton phosphorylation, enabling parasite entry.
Area of Science:
- Molecular parasitology
- Cell biology
- Biochemistry
Background:
- Malaria parasite invasion of red blood cells is an essential step in the pathogen's life cycle.
- Previous research indicated that adenosine triphosphate (ATP) in the host red blood cell cytoplasm is required for parasite entry.
- Parasite binding to red blood cells occurs even without ATP, but entry is inhibited, suggesting ATP's role post-attachment.
Purpose of the Study:
- To investigate the specific role of intracellular adenosine triphosphate (ATP) in the malaria parasite's red blood cell invasion process.
- To explore the hypothesis that ATP regulates the red blood cell membrane cytoskeleton's phosphorylation state during invasion.
- To identify the kinase and substrate involved in ATP-dependent invasion.
Main Methods:
- Utilized red blood cell ghosts, a model system lacking intracellular ATP, to study parasite binding and entry.
- Assessed the activity of membrane-associated cyclic AMP-independent kinase in relation to parasite invasion.
- Investigated potential substrates for this kinase, focusing on cytoskeletal proteins like spectrin.
Main Results:
- Red blood cell ghosts without ATP allowed parasite binding but prevented entry, confirming ATP's necessity for the invasion step after attachment.
- The activity of a specific membrane-associated cyclic AMP-independent kinase was found to be directly correlated with the invasion process.
- Evidence suggests that spectrin, a major component of the red blood cell cytoskeleton, is a likely substrate for this invasion-linked kinase.
Conclusions:
- Intracellular adenosine triphosphate (ATP) is indispensable for the malaria parasite's successful entry into red blood cells, acting after initial recognition and attachment.
- The study provides strong evidence that ATP regulates red blood cell membrane cytoskeleton phosphorylation via a cyclic AMP-independent kinase.
- This kinase activity, potentially acting on spectrin, is a critical host factor enabling malaria parasite invasion.