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Leishmania  parasites are thought to control protein activity at the post-translational level, e.g. by protein phosphorylation. In the pathogenic amastigote, the mammalian stage of  Leishmania  parasites, heat shock proteins show increased phosphorylation, indicating a role in stage-specific signal transduction. Here we investigate the impact of phosphosites in the  L .  donovani  heat shock protein 90. Using a chemical knock-down/genetic complementation approach, we mutated 11 confirmed or presumed phosphorylation sites and assessed the impact on overall fitness, morphology and  in vitro  infectivity. Most phosphosite mutations affected the growth and morphology of promastigotes  in vitro , but with one exception, none of the phosphorylation site mutants had a selective impact on the  in vitro  infection of macrophages. Surprisingly, aspartate replacements mimicking the negative charge of phosphorylated serines or threonines had mostly negative impacts on viability and infectivity. HSP90 is a substrate for casein kinase 1.2-catalysed phosphorylation  in vitro . While several putative phosphosite mutations abrogated casein kinase 1.2 activity on HSP90, only Ser 289  could be identified as casein kinase target by mass spectrometry. In summary, our data show HSP90 as a downstream client of phosphorylation-mediated signalling in an organism that depends on post-transcriptional gene regulation.

Leishmania donovani 90 kD Heat Shock Protein – Impact of Phosphosites on Parasite Fitness, Infectivity and Casein Kinase Affinity