Leishmania Group, Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht St 74, 20359, Hamburg, Germany.
Department of Epidemiology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Sci Rep. 2020 Sep 29;10(1):15969. doi: 10.1038/s41598-020-72724-x.
Leishmania donovani is a trypanosomatidic parasite and causes the lethal kala-azar fever, a neglected tropical disease. The Trypanosomatida are devoid of transcriptional gene regulation and rely on gene copy number variations and translational control for their adaption to changing conditions. To survive at mammalian tissue temperatures, L. donovani relies on the small heat shock protein HSP23, the loss of which renders the parasites stress sensitive and impairs their proliferation. Here, we analysed a spontaneous escape mutant with wild type-like in vitro growth. Further selection of this escape strains resulted in a complete reversion of the phenotype. Whole genome sequencing revealed a correlation between stress tolerance and the massive amplification of a six-gene cluster on chromosome 35, with further analysis showing over expression of the casein kinase 1.2 gene as responsible. In vitro phosphorylation experiments established both HSP23 and the related P23 co-chaperone as substrates and modulators of casein kinase 1.2, providing evidence for another crucial link between chaperones and signal transduction protein kinases in this early branching eukaryote.
杜氏利什曼原虫是一种原生动物寄生虫，可引起致命的黑热病，这是一种被忽视的热带病。原生动物缺乏转录基因调控，依赖基因拷贝数变异和翻译控制来适应环境变化。为了在哺乳动物组织温度下生存，杜氏利什曼原虫依赖于小分子热休克蛋白 HSP23，失去 HSP23 会使寄生虫对压力敏感，并损害其增殖能力。在这里，我们分析了一个具有野生型体外生长特性的自发逃逸突变体。对这种逃逸株的进一步选择导致表型完全逆转。全基因组测序显示，应激耐受性与染色体 35 上六个基因簇的大量扩增之间存在相关性，进一步的分析表明，酪蛋白激酶 1.2 基因的过表达是其原因。体外磷酸化实验证实 HSP23 和相关的 P23 共伴侣是酪蛋白激酶 1.2 的底物和调节剂，为在这个早期分支真核生物中，伴侣蛋白和信号转导蛋白激酶之间的另一个关键联系提供了证据。
