Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion

PLoS Biology
Christian FlueckDavid A Baker

Abstract

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.

References

Dec 1, 1977·The British Journal of Venereal Diseases·T B Turner
Feb 1, 1993·The American Journal of Tropical Medicine and Hygiene·M T Makler, D J Hinrichs
Apr 11, 2003·The Journal of Biological Chemistry·Steven A HowellMichael J Blackman
Apr 24, 2004·Antimicrobial Agents and Chemotherapy·Martin SmilksteinMichael Riscoe
Jul 21, 2004·Molecular Cell·Kam Y J ZhangGideon Bollag
Dec 3, 2005·PLoS Pathogens·Philippa K HarrisMichael J Blackman
Sep 27, 2006·The Journal of Cell Biology·Rebecca A O'DonnellMichael J Blackman
Sep 5, 2008·The Journal of Biological Chemistry·Judith L GreenAnthony A Holder
Jan 24, 2009·PLoS Pathogens·Christine R CollinsMichael J Blackman
Sep 26, 2009·PLoS Pathogens·Robert W MoonOliver Billker
Nov 27, 2009·The Journal of Biological Chemistry·Adebola FalaePurnima Bhanot
Aug 19, 2010·Pharmacological Reviews·Sharron H FrancisDavid Sibley
Oct 23, 2010·Journal of Pineal Research·Marcos L GazariniCélia R S Garcia
Jun 23, 2011·Handbook of Experimental Pharmacology·Hengming KeMengchun Ye
Apr 2, 2014·Nature Reviews. Drug Discovery·Donald H MauriceVincent C Manganiello
Aug 27, 2014·International Journal for Parasitology·Katherine L HarveyBrendan S Crabb
Jan 21, 2015·Molecular Microbiology·Robert StallmachMichael J Blackman

❮ Previous
Next ❯

Citations

Jan 17, 2020·The Biochemical Journal·Sarah J TarrMichael J Blackman
Mar 18, 2020·Life Science Alliance·Konstantinos KoussisMichael J Blackman
Dec 19, 2020·Computational and Structural Biotechnology Journal·Kim Chi VoNishith Gupta
Aug 17, 2021·Frontiers in Cellular and Infection Microbiology·Lucas Silva de OliveiraSébastien Charneau
Sep 27, 2021·Molecular Microbiology·Sylvie BriquetOlivier Silvie

❮ Previous
Next ❯

Datasets Mentioned

BETA
PXD009157

Methods Mentioned

BETA
gene knockout
transgenic
pull-downs
RAP
PCR
flow cytometry
FACS
fluorescence-activated cell sorting
ubiquitination
X-ray

Software Mentioned

Gene Ontologizer
ImageJ
MaxQuant
Perseus
ICY
GraphPad Prism7
FlowJo

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.