Abstract
ABSTRACTThe cyclic GMP-dependent protein kinase (PKG) of apicomplexan parasites is essential for secretion of micronemes and host cell invasion and egress. Both kinase specificity and localization can determine which substrates are phosphorylated. The functions of plasma membrane and cytosolic PKG isoforms of Toxoplasma gondii were unknown because of difficulties precisely manipulating expression of essential genes. Brown et al. (K. M. Brown, S. Long, and L. D. Sibley, mBio 8:e00375-17, https://doi.org/10.1128/mBio.00375-17) adapted the auxin-inducible degron (AID) system for conditional expression of T. gondii proteins. AID, in combination with clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 gene editing, facilitated creation of a panel of PKG mutants to demonstrate that the membrane association via acylation of PKG is critical for its essential functions in tachyzoites. The cytosolic form of PKG is not sufficient for viability and is dispensable. These studies illuminate a critical role for targeting of kinase complexes for parasite viability. The AID system enables rapid, conditional regulation of protein expression that expands the molecular toolbox of T. gondii.
Highlights
The Apicomplexa are obligate intracellular parasites that include important human and veterinary parasites, including Plasmodium species, Cryptosporidium species, and Toxoplasma gondii
Subsequent studies by several groups identified calcium-dependent protein kinases (CDPKs) as regulators of similar pathways, and both PKG and CDPKs have subsequently emerged as important novel targets for antiparasitic agents specific for the Apicomplexa
T. gondii PKG is associated with the cell periphery, and PKG molecular interaction with membranes is based upon acylation by myristate followed by acylation with palmitate (5)
Summary
The Apicomplexa are obligate intracellular parasites that include important human and veterinary parasites, including Plasmodium species, Cryptosporidium species, and Toxoplasma gondii. The era of chemical biology in Apicomplexa was ushered in by elegant work by Gurnett et al (1) and Donald et al (2), who used a novel kinase inhibitor, compound 1, to identify cyclic GMP-dependent protein kinase (PKG) as an essential gene regulating several aspects of apicomplexan parasite biology (3). PKG has a critical role in invasion and microneme secretion for both T. gondii and Plasmodium species (4).
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