Members of the phylum Apicomplexa are of considerable medical and veterinary significance, being responsible for severe diseases in humans and animals. These parasites have adopted an obligate intracellular lifestyle and rely on a common active mode of host cell entry that offers them a unique opportunity to infect a broad range of cell types without stimulating host cell defense mechanisms.
Actomyosin-Based Motility and Organelles Biogenesis in Apicomplexa
Actin and myosins are implicated in a broad range of essential cellular processes, including cell motility, cell division, organelle movement, and chromosome segregation. Apicomplexan parasites possess a repertoire of poorly characterized exotic myosin motors that likely are associated with parasite-specific processes. In the absence of normal appendages for locomotion, such as cilia and flagella, the invasive stages of these parasites use gliding motility to power their migration across biological barriers, to invade host cells, and to egress from infected cells. The conserved molecular machinery that generates motion, called the "glideosome," involves the action of signaling molecules, myosin A and its associated proteins, regulators of actin dynamics, secreted adhesins, and proteases. Apicomplexans also share several myosin motors that are implicated in fundamental biological processes, such as organelle biogenesis and inheritance. In Toxoplasma gondii, the segregation of the plastid-like organelle called apicoplast occurs early during endodyogeny and coincides with nuclear division and daughter cell budding. This organelle is anchored to the centrosomes and associates with the mitotic spindle. Several experimental approaches that perturb actin dynamics lead to a severe impairment in apicoplast inheritance. Myosin F has been identified as a key motor associated with this process. In contrast to the apicoplast, rhoptries are formed de novo at a late stage of cell division, presumably by vesicular budding from the Golgi apparatus. These specialized secretory organelles not only contribute to moving junction—and parasitophorous vacuole membrane—formation but also send effector molecules into the host cell, critically affecting virulence. A conserved protein containing Armadillo repeats is anchored at the surface of the rhoptries via acylation and plays a critical role in positioning the organelle at the apical tip of the parasite. This protein potentially associates with a myosin motor that remains to be identified.
Importance of Protein Palmitoylation in the Biology of Apicomplexa
Protein S-palmitoylation involves the addition of a 16 carbon atoms fatty acid to cysteine residues via a thioester bond and confers an increased hydrophobicity on proteins. The reversible nature of palmitoylation has recently emerged as an important mode of control for biological processes, affecting protein trafficking, stability folding, signaling, and interactions. In T. gondii, key proteins implicated in motility, invasion, and organelle biogenesis are predicted to be palmitoylated. Whereas depalmitoylation involves one or a few acyl-thioesterases, palmitoylation is catalyzed by a large family of multimembrane palmitoyl acyl transferases (PATs) exhibiting a catalytic Asp-His-His-Cys (DHHC) motif that mediates the transfer of palmitate from palmitoyl-CoA to specific substrates. T. gondii possesses 18 genes coding for DHHC proteins predicted to act as protein acyl transferases. These DHHC family members localize to the Golgi, the inner membrane complex, the endoplasmic reticulum, the plasma membrane, and the rhoptries. We are dissecting several palmitoylated proteins localized to different these subcellular compartments to obtain insight into the mode of PAT substrate specificity. Several putative PATs appear to be essential for parasite survival, a finding consistent with a broad and critical impact of palmitoylation on the lytic cycle of these parasites.
As of September 26, 2012