Leishmania phosphatase PP5 is a regulator of HSP83 phosphorylation and essential for parasite pathogenicity
Leishmania parasites are responsible for important neglected diseases in humans and animals, ranging from self-healing cutaneous lesions to fatal visceral manifestations. During the infectious cycle, Leishmania differentiates from the extracellular flagellated promastigote to the intracellular pathogenic amastigote. Parasite differentiation is triggered by changes in environmental cues, mainly pH and temperature. In general, extracellular signals are translated into stage-specific gene expression by a cascade of reversible protein phosphorylation regulated by protein kinases and phosphatases. Though protein kinases have been actively studied as potential anti-parasitic drug targets, our understanding of the biology of protein phosphatases in Leishmania is poor. We have previously reported the principal analysis of a novel protein phosphatase 5 (PP5) in Leishmania species. Here, we assessed the role of PP5 in parasite pathogenicity, where we uncovered, using transgenic PP5 over-expressing and PP5 null-mutant parasites, its importance in metacyclogeneisis, maintaining HSP83 phosphorylation homeostasis and virulence. All together, our results indicate the importance of PP5 in regulating parasite stress and adaptation during differentiation, making this protein an attractive potential target for therapeutic intervention.
KeywordsLeishmania Stress response Phosphatase Virulence Drug target
This work was supported by the Eck Institute of Global Health and capitalization funds from the University of Notre Dame to MAM. All authors declare no financial/commercial conflict of interest. We thank Prof. Steve Beverley (Washington University of St Louis, USA) for the pXNG system.
Compliance with ethical standards
The University of Notre Dame is credited through the Animal Welfare Assurance (#A3093-01). All animal studies were conducted according to the Institutional Animal Care and Use Committee (IACUC) guidelines. The protocol for the infection of mice with Leishmania was approved by the University’s IACUC (September 27, 2017, protocol #15-10-2708).
Conflict of interest
The authors declare that they have no conflict of interest.
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