A pH-dependent protein kinase cascade regulates divergent differentiation of Leishmania in the sand fly.
- 1University of York
Abstract
Leishmania parasites must rapidly adapt to fluctuating environments to ensure survival and transmission. While acidic pH in the sand fly vector is a conserved developmental trigger, sensing mechanisms remain poorly understood. Using a barcoded protein kinase library, we screened for regulators of acid adaptation in Leishmania mexicana, identifying nine protein kinases influencing survival at low pH, including a haptomonad differentiation regulator protein kinase (HDRK1). We demonstrate that HDRK1 null mutants ({Delta}hdrk1) are predisposed to differentiate to haptomonad-like forms at low pH. While {Delta}hdrk1 mutants successfully infect the sand fly midgut, they fail to colonise the stomodeal valve, compromising transmission. Integrated transcriptomic and proteomic analyses revealed that at low pH, {Delta}hdrk1 mutants enter a low energy state reminiscent of AMPK-activated cells. We identified a second protein kinase, HDRK2, establishing a pH-dependent signalling pathway that governs the developmental fate of the parasite, directing differentiation towards either mammalian-infective metacyclic or vector-attached haptomonad stages. Finally, our screen revealed that phosphoinositide balance, regulated by the lipid kinases PI4K and PI4P5K, is vital for acid adaptation, and identified two STE transmembrane kinases as potential pH sensors. Together these findings provide a framework for how Leishmania detects and survives acid stress to coordinate its life cycle.
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BibTeX
@misc{liz2026phdependent,
title = {{A pH-dependent protein kinase cascade regulates divergent differentiation of Leishmania in the sand fly.}},
author = {L. V. de Liz and J. Sadlova and B. Becvarova and J. A. Brannigan and S. Forrester and C. McNiven and A. Dowle and c. Taylor and A. J. Wilkinson and P. Volf and J. C. Mottram and N. Baker},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751656},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751656v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A pH-dependent protein kinase cascade regulates divergent differentiation of Leishmania in the sand fly.
AU - L. V. de Liz
AU - J. Sadlova
AU - B. Becvarova
AU - J. A. Brannigan
AU - S. Forrester
AU - C. McNiven
AU - A. Dowle
AU - c. Taylor
AU - A. J. Wilkinson
AU - P. Volf
AU - J. C. Mottram
AU - N. Baker
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751656
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751656v1
AB - Leishmania parasites must rapidly adapt to fluctuating environments to ensure survival and transmission. While acidic pH in the sand fly vector is a conserved developmental trigger, sensing mechanisms remain poorly understood. Using a barcoded protein kinase library, we screened for regulators of acid adaptation in Leishmania mexicana, identifying nine protein kinases influencing survival at low pH, including a haptomonad differentiation regulator protein kinase (HDRK1). We demonstrate that HDRK1 null mutants ({Delta}hdrk1) are predisposed to differentiate to haptomonad-like forms at low pH. While {Delta}hdrk1 mutants successfully infect the sand fly midgut, they fail to colonise the stomodeal valve, compromising transmission. Integrated transcriptomic and proteomic analyses revealed that at low pH, {Delta}hdrk1 mutants enter a low energy state reminiscent of AMPK-activated cells. We identified a second protein kinase, HDRK2, establishing a pH-dependent signalling pathway that governs the developmental fate of the parasite, directing differentiation towards either mammalian-infective metacyclic or vector-attached haptomonad stages. Finally, our screen revealed that phosphoinositide balance, regulated by the lipid kinases PI4K and PI4P5K, is vital for acid adaptation, and identified two STE transmembrane kinases as potential pH sensors. Together these findings provide a framework for how Leishmania detects and survives acid stress to coordinate its life cycle.
ER -