Dense granule biogenesis, secretion, and function in Toxoplasma gondii

Abstract

Toxoplasma gondii is an obligate intracellular parasite and the causative agent of Toxoplasmosis. A key to understanding and treating the disease lies with determining how the parasite can survive and replicate within cells of its host. Proteins released from specialized secretory vesicles, named the dense granules (DGs), have diverse functions that are critical for adapting the intracellular environment, and are thus key to survival and pathogenicity. In this review, we describe the current understanding and outstanding questions regarding dense granule biogenesis, trafficking, and regulation of secretion. In addition, we provide an overview of dense granule protein (“GRA”) function upon secretion, with a focus on proteins that have recently been identified.

Phosphatidylinositol-4-phosphate signaling regulates dense granule biogenesis and exocytosis inToxoplasma gondii

“…Moreover, we show that compromised PtdIns4P signaling results in structural perturbation of DGs with accompanying deficits in exocytosis of DG cargo. Taken together, the data not only demonstrate that PtdIns4P itself is a key regulator of DG biogenesis and exocytosis, but also suggest that the biogenic pathway for DG formation in T. gondii is more complex than simple budding from the TGN -- as is presently proposed (Griffith et al, 2022). Finally, the collective results argue for a primordial role for PtdIns4P signaling in membrane trafficking through the late stages of the secretory pathway – a role that has been preserved throughout the Eukaryota from yeast to primates.…”

“…Current models envision formation of DGs to result via direct budding from the T. gondii TGN as mature structures with appropriately sorted and condensed cargo (Griffith et al, 2022). Thus, DGs are not considered to undergo the types of more complex maturation processes that are hallmarks of dense core vesicle compartments that form the basis of regulated exocytosis systems of other eukaryotes – e.g.…”

Functional Characterization of 15 Novel Dense Granule Proteins in Toxoplasma gondii Using the CRISPR-Cas9 System

“…The majority of GRAs are synthesized in the rough ER and then exported from the ER, trafficking through the Golgi to the dense granules, then finally secreted from the parasite to a particular location to perform its function ( 23 ). In this study, subcellular localizations of 15 novel GRAs were investigated in the tachyzoites and bradyzoites of the T. gondii RH strain.…”

“…Small nutrient molecules are absorbed through membrane pores formed by GRA17 and GRA23 on the PVM (22). Some GRAs are trafficked across the PVM into the host nucleus cytosol and play important roles in modifying the host signaling pathways, regulation of gene expression, and modulation of host cell immunity (4,7,9,23). For example, GRA16, GRA24, Toxoplasma inhibitor of STAT1-dependent transcription (TgIST) and Toxoplasma E2F4-associated EZH2inducing gene regulator (TEEGR) (synonymous with inducer of host cyclin E 1 [HCE1]) are exported beyond the PVM and translocated into host cell nuclei (4,(24)(25)(26)(27)(28)(29).…”

The determinants regulating Toxoplasma gondii bradyzoite development

“…In addition, many GRAs are associated with tachyzoite PVM and IVN. During bradyzoite differentiation, they relocate to the cyst wall and ICN (Griffith et al, 2022), raising the possibility of a close structural correlation between vacuole and cyst. But it is unclear whether the PVM is equivalent to the cyst wall or IVN is equal to ICN, the biogenesis of T. gondii vacuole and cyst and their correlations need further study.…”