Abstract
SummaryHSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. Four HSP90 isoforms were identified in the protozoan parasite Theileria annulata. Partial characterization was undertaken for three and localization confirmed for cytoplasmic (TA12105), endoplasmic reticulum (TA06470), and apicoplast (TA10720) forms. ATPase activity and binding to the HSP90 inhibitor geldanamycin were demonstrated for recombinant TA12105, and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. Resistance to the only specific Theileriacidal drug is increasing, and one challenge for design of drugs that target the parasite is to limit the effect on the host. An in vitro cell culture system that allows comparison between uninfected bovine cells and the T. annulata‐infected counterpart was utilized to test the effects of geldanamycin and the derivative 17‐AAG. T. annulata‐infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17‐AAG. These findings suggest that parasite HSP90 isoform(s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation.
Highlights
Chaperone proteins are fundamental to the enablement of conformational changes in a wide range of cellular effector proteins, especially under conditions of stress (Morimoto, 1998; Kennedy, Jäger, Mosser, & Samali, 2014)
HSP90 chaperones, are known for their tendency to interact with specific proteins involved in essential cellular regulation under non‐ stress conditions: client proteins include nuclear hormone receptors, kinases, and transcription factors (Pearl & Prodromou, 2006)
T. annulata undergoes several stage differentiation events during its life cycle that require adaptation to different cellular environments: a sexual cycle occurs in the tick vector, followed by generation of the sporozoite stage in the salivary glands; invasion of the bovine leukocyte by the sporozoite, followed by differentiation to a multinucleate intracellular macroschizont; a switch from the macroschizont stage to production of uni‐nucleate merozoites; invasion of erythrocytes and development into piroplasms, a life cycle stage that may represent gametocytes that are transmitted to the tick vector on feeding (reviewed in (Dobbelaere & Heussler, 1999))
Summary
HSP90 chaperones are essential regulators of cellular function, as they ensure the appropriate conformation of multiple key client proteins. ATPase activity and binding to the HSP90 inhibitor geldanamycin were demonstrated for recombinant TA12105, and all three native forms could be isolated to varying extents by binding to geldanamycin beads. Because it is essential, HSP90 is considered a potential therapeutic drug target. T. annulata‐infected cells had greater tolerance to geldanamycin than uninfected cells yet exhibited significantly more sensitivity to 17‐AAG. These findings suggest that parasite HSP90 isoform(s) can alter the drug sensitivity of infected host cells and that members of the Theileria HSP90 family are potential targets worthy of further investigation
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