Cyclic nucleotide signalling in malaria parasites

Baker, David A.; Drought, Laura; Flueck, Christian; Nofal, Stephanie D.; Patel, Avnish; Penzo, Maria; Walker, E. A.

doi:10.1098/rsob.170213

Cited by 70 publications

(69 citation statements)

References 106 publications

(197 reference statements)

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“…Apicomplexan parasites have adapted cyclic nucleotide signaling to precisely regulate the timing and amplitude of essential motile processes (Baker et al, 2017), yet it is unclear how these signals are actually initiated in these organisms. Here we performed a reverse genetic screen of enzymes predicted to synthesize cyclic nucleotides in the model apicomplexan T. gondii.…”

Section: Discussionmentioning

confidence: 99%

Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase

Brown

Sibley

2018

Cell Host & Microbe

101

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Summary (150) Apicomplexan parasites rely on cyclic nucleotide-dependent kinases for host cell infection, yet the mechanisms that control their activation remain unknown. Here we show that an apically-localized guanylate cyclase (GC) controls microneme secretion and lytic growth in the model apicomplexan Toxoplasma gondii. Cell permeable cGMP reversed the block in microneme secretion seen in a knockdown of TgGC, linking its function to production of cGMP. TgGC possesses an N-terminal P-type-ATPase domain fused to a C-terminal heterodimeric guanylate cyclase domain, an architecture found only in Apicomplexa and related protists. Complementation with a panel of mutants revealed a critical requirement for the P-type ATPase domain for maximum GC function. We further demonstrate that knockdown of TgGC in vivo protects mice from lethal infection by blocking parasite expansion and dissemination. Collectively this work demonstrates that cGMP-mediated signaling in Toxoplasma relies on a multi-domain architecture, which may serve a conserved role in related parasites.

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Section: Discussionmentioning

confidence: 99%

Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase

Brown

Sibley

2018

Cell Host & Microbe

101

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“…These free‐living protists exhibited targeted impacts on chemosensation with the inhibition of G‐protein coupled receptor signalling and both chemsensation and predation with the inhibition of protein kinase signal transduction. In the apicomplexan malarial parasite Plasmodium , cyclic nucleotide signalling is critical for the control of every stage of parasite life, with kinases mediating the response to diverse extracellular stimuli (reviewed by Baker, ; Billker, Lourido, & Sibley, ). While their enhanced activity in the free‐living state suggests the importance of extracellular perception through gPCRs and other cell surface receptors, we suggest that an in hospite symbiont may in some ways resemble an organelle, as it persists within a host‐derived membrane (Wakefield & Kempf, ) and is housed for a specific function within a host cell.…”

Section: Discussionmentioning

confidence: 99%

Free‐living and symbiotic lifestyles of a thermotolerant coral endosymbiont display profoundly distinct transcriptomes under both stable and heat stress conditions

et al. 2019

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Reef‐building corals depend upon a nutritional endosymbiosis with photosynthetic dinoflagellates of the family Symbiodiniaceae for the majority of their energetic needs. While this mutualistic relationship is impacted by numerous stressors, warming oceans are a predominant threat to coral reefs, placing the future of the world's reefs in peril. Some Symbiodiniaceae species exhibit tolerance to thermal stress, but the in hospite symbiont response to thermal stress is underexplored. To describe the underpinnings of symbiosis and heat stress response, we compared in hospite and free‐living transcriptomes of Durusdinium trenchii, a pan‐tropical heat‐tolerant Symbiodiniaceae species, under stable temperature conditions and acute hyperthermal stress. We discovered that symbiotic state was a larger driver of the transcriptional landscape than heat stress. The majority of differentially expressed transcripts between in hospite and free‐living cells were downregulated, suggesting the in hospite condition is associated with the shutdown of numerous processes uniquely required for a free‐living lifestyle. In the free‐living state, we identified enrichment for numerous cell signalling pathways and other functions related to detecting and responding to a changing environment, as well as transcripts relating to mitosis, meiosis, and motility. In contrast, in hospite cells exhibited enhanced transcriptional activity for photosynthesis and carbohydrate transport as well as chromatin modifications and a disrupted circadian clock. Hyperthermal stress induced drastic alteration of transcriptional activity in hospite, suggesting symbiotic engagement with the host elicited an exacerbated stress response when compared to free‐living D. trenchii. Altogether, the dramatic differences in gene expression between in hospite and free‐living D. trenchii indicate the importance of considering symbiotic state in investigations of symbiosis and hyperthermal stress in Symbiodiniaceae.

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“…Recently, phosphatidic acid (PA) produced through phosphorylation of diacylglycerol by DGK1 was also shown to critically contribute to microneme exocytosis (Bullen et al , ). A role for cyclic adenosine monophosphate (cAMP)‐dependent signalling to control egress and invasion in Apicomplexa has been suspected but remains largely uncharacterised (Baker, ).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between PKA and PKG controls pH ‐dependent host cell egress of Toxoplasma gondii

et al. 2017

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Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1-3) and one regulatory (PKAr) subunits to integrate cAMP-dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down-regulation of PKAc1 or stabilisation of a dominant-negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP-phosphodiesterase. Concordantly, inhibition of the cGMP-dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP-phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii.

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Cyclic nucleotide signalling in malaria parasites

Cited by 70 publications

References 106 publications

Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase

Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase

Free‐living and symbiotic lifestyles of a thermotolerant coral endosymbiont display profoundly distinct transcriptomes under both stable and heat stress conditions

Crosstalk between PKA and PKG controls pH ‐dependent host cell egress of Toxoplasma gondii

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