Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion.
Cyclic nucleotide signalling is a major regulator of malaria parasite differentiation. Phosphodiesterase (PDE) enzymes are known to control cyclic GMP (cGMP) levels in the parasite, but the mechanisms by which cyclic AMP (cAMP) is regulated remain enigmatic. Here, we demonstrate that Plasmodium falc...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-02-01
|
| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3000154 |
| _version_ | 1818361541200707584 |
|---|---|
| author | Christian Flueck Laura G Drought Andrew Jones Avnish Patel Abigail J Perrin Eloise M Walker Stephanie D Nofal Ambrosius P Snijders Michael J Blackman David A Baker |
| author_facet | Christian Flueck Laura G Drought Andrew Jones Avnish Patel Abigail J Perrin Eloise M Walker Stephanie D Nofal Ambrosius P Snijders Michael J Blackman David A Baker |
| author_sort | Christian Flueck |
| collection | DOAJ |
| description | Cyclic nucleotide signalling is a major regulator of malaria parasite differentiation. Phosphodiesterase (PDE) enzymes are known to control cyclic GMP (cGMP) levels in the parasite, but the mechanisms by which cyclic AMP (cAMP) is regulated remain enigmatic. Here, we demonstrate that Plasmodium falciparum phosphodiesterase β (PDEβ) hydrolyses both cAMP and cGMP and is essential for blood stage viability. Conditional gene disruption causes a profound reduction in invasion of erythrocytes and rapid death of those merozoites that invade. We show that this dual phenotype results from elevated cAMP levels and hyperactivation of the cAMP-dependent protein kinase (PKA). Phosphoproteomic analysis of PDEβ-null parasites reveals a >2-fold increase in phosphorylation at over 200 phosphosites, more than half of which conform to a PKA substrate consensus sequence. We conclude that PDEβ plays a critical role in governing correct temporal activation of PKA required for erythrocyte invasion, whilst suppressing untimely PKA activation during early intra-erythrocytic development. |
| first_indexed | 2024-12-13T21:18:19Z |
| format | Article |
| id | doaj.art-f2dfa91a00fe4670be575d3637a30657 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-13T21:18:19Z |
| publishDate | 2019-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-f2dfa91a00fe4670be575d3637a306572022-12-21T23:31:12ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852019-02-01172e300015410.1371/journal.pbio.3000154Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion.Christian FlueckLaura G DroughtAndrew JonesAvnish PatelAbigail J PerrinEloise M WalkerStephanie D NofalAmbrosius P SnijdersMichael J BlackmanDavid A BakerCyclic nucleotide signalling is a major regulator of malaria parasite differentiation. Phosphodiesterase (PDE) enzymes are known to control cyclic GMP (cGMP) levels in the parasite, but the mechanisms by which cyclic AMP (cAMP) is regulated remain enigmatic. Here, we demonstrate that Plasmodium falciparum phosphodiesterase β (PDEβ) hydrolyses both cAMP and cGMP and is essential for blood stage viability. Conditional gene disruption causes a profound reduction in invasion of erythrocytes and rapid death of those merozoites that invade. We show that this dual phenotype results from elevated cAMP levels and hyperactivation of the cAMP-dependent protein kinase (PKA). Phosphoproteomic analysis of PDEβ-null parasites reveals a >2-fold increase in phosphorylation at over 200 phosphosites, more than half of which conform to a PKA substrate consensus sequence. We conclude that PDEβ plays a critical role in governing correct temporal activation of PKA required for erythrocyte invasion, whilst suppressing untimely PKA activation during early intra-erythrocytic development.https://doi.org/10.1371/journal.pbio.3000154 |
| spellingShingle | Christian Flueck Laura G Drought Andrew Jones Avnish Patel Abigail J Perrin Eloise M Walker Stephanie D Nofal Ambrosius P Snijders Michael J Blackman David A Baker Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion. PLoS Biology |
| title | Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion. |
| title_full | Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion. |
| title_fullStr | Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion. |
| title_full_unstemmed | Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion. |
| title_short | Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion. |
| title_sort | phosphodiesterase beta is the master regulator of camp signalling during malaria parasite invasion |
| url | https://doi.org/10.1371/journal.pbio.3000154 |
| work_keys_str_mv | AT christianflueck phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT lauragdrought phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT andrewjones phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT avnishpatel phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT abigailjperrin phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT eloisemwalker phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT stephaniednofal phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT ambrosiuspsnijders phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT michaeljblackman phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion AT davidabaker phosphodiesterasebetaisthemasterregulatorofcampsignallingduringmalariaparasiteinvasion |