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

Abstract

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.

Adapt or Die: Targeting Unique Transmission-Stage Biology for Malaria Elimination

“…The PKG mediated cascade (including involvement of Pf PI4K and phosphatidylinositol 4-phosphate 5-kinase, PIP5K) results ultimately in opening of IP 3 -gated calcium channels on the ER and a resultant increase in intracellular Ca 2+ ( Bennink et al., 2016 ). Activation of several sex-specific CDPKs ensues ( Brochet et al., 2021 ), including CDPK1-mediated release of DOZI, CITH and Pf Puf2 for translation in female gametes and CDPK4 to activate cyclins and cyclin-dependent kinases for cell division in male gametes ( Kumar et al., 2021 ) ( Figure 4 ). The latter is mediated by successive S and M cell cycle phases ( Raabe et al., 2009 ; Meibalan and Marti, 2017 ).…”

Functional Analysis of the Expanded Phosphodiesterase Gene Family in Toxoplasma gondii Tachyzoites

“…Apicomplexans have adapted second messenger signaling systems to regulate microneme secretion and motility (11)(12)(13)(14)(15). Purine cyclic nucleotides (cGMP and cAMP) and ionic calcium (Ca 2+ ) signaling pathways are central regulators of apicomplexan motility, but there are species-dependent variations in how they operate.…”

The Skp1-Cullin1-FBXO1 complex is a pleiotropic regulator required for the formation of gametes and motile forms in Plasmodium berghei

“…However, key aspects of cellular development also require posttranslational modifications (PTMs) of proteins 10 . Multiple PTMs have been shown to be important for developmental transitions, including phosphorylation, acetylation, methylation, and lipidation [10][11][12] , but little is known about the requirement of ubiquitination in Plasmodium. Mass spectrometry-based approaches identified snapshots of ubiquitinated proteins in Plasmodium 13,14 .…”