Chimeras of P4-ATPase and Guanylate Cyclase in Pathogenic Protists

Günay-Esiyok, Özlem; Gupta, Nishith

doi:10.1016/j.pt.2020.01.009

Cited by 5 publications

(2 citation statements)

References 74 publications

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“…Sequence analysis of the B. microti genome, which is the smallest apicomplexan genome sequenced to date, revealed conserved cyclic nucleotide signaling genes. B. microti encodes one GC (BMR1_03g00165) with the prototypical P4-ATPase-GCα architecture found in apicomplexans and other protists ( 99 ) and one AC (BMR1_04g07620) containing two N-terminal cyclase homology domains, resembling ACβs in other apicomplexans like Toxoplasma , Plasmodium , and Cryptosporidium . To respond to cGMP, B. microti encodes one PKG (BMR1_04g05785).…”

Section: Cyclic Nucleotide Signaling In Cryptosporidium ...mentioning

confidence: 99%

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential

Moss,

Brusini,

Kuehnel

et al. 2024

mBio

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Apicomplexa encompasses a large number of intracellular parasites infecting a wide range of animals. Cyclic nucleotide signaling is crucial for a variety of apicomplexan life stages and cellular processes. The cyclases and kinases that synthesize and respond to cyclic nucleotides (i.e., 3′,5′-cyclic guanosine monophosphate and 3′,5′-cyclic adenosine monophosphate) are highly conserved and essential throughout the parasite phylum. Growing evidence indicates that phosphodiesterases (PDEs) are also critical for regulating cyclic nucleotide signaling via cyclic nucleotide hydrolysis. Here, we discuss recent advances in apicomplexan PDE biology and opportunities for therapeutic interventions, with special emphasis on the major human apicomplexan parasite genera Plasmodium , Toxoplasma , Cryptosporidium , and Babesia . In particular, we show a highly flexible repertoire of apicomplexan PDEs associated with a wide range of cellular requirements across parasites and lifecycle stages. Despite this phylogenetic diversity, cellular requirements of apicomplexan PDEs for motility, host cell egress, or invasion are conserved. However, the molecular wiring of associated PDEs is extremely malleable suggesting that PDE diversity and redundancy are key for the optimization of cyclic nucleotide turnover to respond to the various environments encountered by each parasite and life stage. Understanding how apicomplexan PDEs are regulated and integrating multiple signaling systems into a unified response represent an untapped avenue for future exploration.

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Section: Cyclic Nucleotide Signaling In Cryptosporidium ...mentioning

confidence: 99%

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential

Moss,

Brusini,

Kuehnel

et al. 2024

mBio

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show abstract

“…This suggests that, as in Plasmodium gametocytes, cGMP synthesis, and hydrolysis are active at a steady state level. Three recent studies have shown that a single guanylyl cyclase (TgGC) is the only essential cyclase upstream of PKG in the tachyzoite stage (Bisio et al, 2019; Brown & Sibley, 2018; Günay‐Esiyok et al, 2019), reviewed in (Günay‐Esiyok & Gupta, 2020). TgGC shows the same organization as Plasmodium GCs with a P4‐ATPase and two GC catalytic domains.…”

Section: A Conserved Sensing Pathway Across Plasmodium Stages and Apicomplexans?mentioning

confidence: 99%

cGMP homeostasis in malaria parasites—The key to perceiving and integrating environmental changes during transmission to the mosquito

Brochet

Balestra

Brusini

2020

Molecular Microbiology

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Malaria‐causing parasites are transmitted from humans to mosquitoes when developmentally arrested gametocytes are taken up by a female Anopheles during a blood meal. The changes in environment from human to mosquito activate gametogenesis, including a drop in temperature, a rise in pH, and a mosquito‐derived molecule, xanthurenic acid. Signaling receptors have not been identified in malaria parasites but mounting evidence indicates that cGMP homeostasis is key to sensing extracellular cues in gametocytes. Low levels of cGMP maintained by phosphodiesterases prevent precocious activation of gametocytes in the human blood. Upon ingestion, initiation of gametogenesis depends on the activation of a hybrid guanylyl cyclase/P4‐ATPase. Elevated cGMP levels lead to the rapid mobilization of intracellular calcium that relies upon the activation of both cGMP‐dependent protein kinase and phosphoinositide phospholipase C. Once calcium is released, a cascade of phosphorylation events mediated by calcium‐dependent protein kinases and phosphatases regulates the cellular processes required for gamete formation. cGMP signaling also triggers timely egress from the host cell at other life cycle stages of malaria parasites and in Toxoplasma gondii, a related apicomplexan parasite. This suggests that cGMP signaling is a versatile platform transducing external cues into calcium signals at important decision points in the life cycle of apicomplexan parasites.

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The protozoan parasite Toxoplasma gondii encodes a gamut of phosphodiesterases during its lytic cycle in human cells

Günay-Esiyok

Liem

et al. 2020

Computational and Structural Biotechnology Journal

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Chimeras of P4-ATPase and Guanylate Cyclase in Pathogenic Protists

Cited by 5 publications

References 74 publications

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential

cGMP homeostasis in malaria parasites—The key to perceiving and integrating environmental changes during transmission to the mosquito

The protozoan parasite Toxoplasma gondii encodes a gamut of phosphodiesterases during its lytic cycle in human cells

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