Leishmania phosphatase PP5 is a regulator of HSP83 phosphorylation and essential for parasite pathogenicity

Abstract

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.

Involvement of Leishmania Phosphatases in Parasite Biology and Pathogeny

“…PP5 is a unique member of the PPP family due to the presence of an N-terminal tetratricopeptide repeat (TPR) domain that is involved in protein-protein interactions (Borthwick et al, 2001). Recently, it was observed that PP5 plays a role in the metacyclogenesis and virulence of Leishmania parasites (Norris-Mullins et al, 2018). L. donovani axenic metacyclic promastigotes present an increase in PP5 expression when compared to procyclic promastigote and amastigote stages.…”

“…Although DPP5 promastigotes retain the ability to differentiate, a significant increase in premature cell death was observed. The relevance of PP5 during the differentiation process seems to be related to its interaction with the heat-shock protein HSP83 (Norris-Mullins et al, 2018). To investigate the potential consequences of the abolishment of PP5 on the pathobiology of Leishmania, in vitro and in vivo assays were performed with L. donovani and L. major, respectively.…”

“…To investigate the potential consequences of the abolishment of PP5 on the pathobiology of Leishmania, in vitro and in vivo assays were performed with L. donovani and L. major, respectively. Although DPP5 L. donovani parasites have been able to successfully invade murine macrophages, an attenuation in the virulence of DPP5 L. major parasites was demonstrated through a well-established cutaneous leishmaniasis model system (Norris-Mullins et al, 2018).…”

“…The requirement of calcium uptake FIGURE 1 | Physiological roles described for Leishmania endogenous phosphatases. Phosphatases may contribute to the ability of parasites to adapt properly during stress conditions, favoring the differentiation process (Martin et al, 2014;Inbar et al, 2017;Norris-Mullins et al, 2018). Whole-genome expression analyses revealed that several Leishmania phosphatases are upregulated in nectomonad and metacyclic promastigotes (Saxena et al, 2003;Alcolea et al, 2009;Dillon et al, 2015;Inbar et al, 2017).…”

“…Different STPs expressed by Leishmania parasites have been identified and characterized by biochemical and molecular means, including protein phosphatase 5 (PP5) (Norris-Mullins et al, 2018), protein phosphatase 1 (PP1) (Qureshi et al, 2019), protein phosphatase 2C (PP2C) (Jakkula et al, 2018), and protein phosphatase 2B (PP2B) (Banerjee et al, 1999) of Leishmania donovani; PP2B (Naderer et al, 2011), protein phosphatase with EF-Hand (PPEF) (Mills et al, 2007), and arsenate reductase 2 (ACR2) (Zhou et al, 2004;Zhou et al, 2006) of Leishmania major; PP2C (Escalona-Montaño et al, 2016) of Leishmania mexicana; and PP2C (Burns et al, 1993) of Leishmania chagasi.…”