Leishmania dual‐specificity tyrosine‐regulated kinase 1 (DYRK1) is required for sustaining Leishmania stationary phase phenotype

Although the multiplicative and growth‐arrested states play key roles in Leishmania development, the regulators of these transitions are largely unknown. In an attempt to gain a better understanding of these processes, we characterised one member of a family of protein kinases with dual specificity, LinDYRK1, which acts as a stasis regulator in other organisms. LinDYRK1 overexpressing parasites displayed a decrease in proliferation and in cell cycle re‐entry of arrested cells. Parasites lacking LinDYRK1 displayed distinct fitness phenotypes in logarithmic and stationary growth phases. In logarithmic growth phase, LinDYRK1−/− parasites proliferated better than control lines, supporting a role of this kinase in stasis, while in stationary growth phase, LinDYRK1−/− parasites had important defects as they rounded up, accumulated vacuoles and lipid bodies and displayed subtle but consistent differences in lipid composition. Moreover, they expressed less metacyclic‐enriched transcripts, displayed increased sensitivity to complement lysis and a significant reduction in survival within peritoneal macrophages. The distinct LinDYRK1−/− growth phase phenotypes were mirrored by the distinct LinDYRK1 localisations in logarithmic (mainly in flagellar pocket area and endosomes) and late stationary phase (mitochondrion). Overall, this work provides first evidence for the role of a DYRK family member in sustaining promastigote stationary phase phenotype and infectivity. Dual‐specificity tyrosine (Y) phosphorylation‐regulated kinase (DYRK) kinases are important stasis regulators. The absence of DYRK1 kinase activity in Leishmania promastigotes correlates with several defects in morphology, cell cycle and lipid composition, metacyclogenesis and virulence. DYRK1 overexpression and deletion, results in retardation and acceleration of promastigote growth respectively. Thus, our data describe a role for Leishmania DYRK1 in mediating growth/arrest transitions and a requirement of its activity is essential for normal Leishmania stationary phase development.