TORC1 is an essential regulator of nutrient-controlled proliferation and differentiation in Leishmania

TY - JOUR

T1 - TORC1 is an essential regulator of nutrient-controlled proliferation and differentiation in Leishmania

AU - Myburgh, Elmarie

AU - Geoghegan, Vincent

AU - Alves-Ferreira, Eliza Vc

AU - Nievas, Y Romina

AU - Grewal, Jaspreet S

AU - Brown, Elaine

AU - McLuskey, Karen

AU - Mottram, Jeremy C

N1 - © 2024. The Author(s).

PY - 2024/3/12

Y1 - 2024/3/12

N2 - Leishmania parasites undergo differentiation between various proliferating and non-dividing forms to adapt to changing host environments. The mechanisms that link environmental cues with the parasite's developmental changes remain elusive. Here, we report that Leishmania TORC1 is a key environmental sensor for parasite proliferation and differentiation in the sand fly-stage promastigotes and for replication of mammalian-stage amastigotes. We show that Leishmania RPTOR1, interacts with TOR1 and LST8, and identify new parasite-specific proteins that interact in this complex. We investigate TORC1 function by conditional deletion of RPTOR1, where under nutrient-rich conditions RPTOR1 depletion results in decreased protein synthesis and growth, G1 cell cycle arrest and premature differentiation from proliferative promastigotes to non-dividing mammalian-infective metacyclic forms. These parasites are unable to respond to nutrients to differentiate into proliferative retroleptomonads, which are required for their blood-meal induced amplification in sand flies and enhanced mammalian infectivity. We additionally show that RPTOR1-/- metacyclic promastigotes develop into amastigotes but do not proliferate in the mammalian host to cause pathology. RPTOR1-dependent TORC1 functionality represents a critical mechanism for driving parasite growth and proliferation.

AB - Leishmania parasites undergo differentiation between various proliferating and non-dividing forms to adapt to changing host environments. The mechanisms that link environmental cues with the parasite's developmental changes remain elusive. Here, we report that Leishmania TORC1 is a key environmental sensor for parasite proliferation and differentiation in the sand fly-stage promastigotes and for replication of mammalian-stage amastigotes. We show that Leishmania RPTOR1, interacts with TOR1 and LST8, and identify new parasite-specific proteins that interact in this complex. We investigate TORC1 function by conditional deletion of RPTOR1, where under nutrient-rich conditions RPTOR1 depletion results in decreased protein synthesis and growth, G1 cell cycle arrest and premature differentiation from proliferative promastigotes to non-dividing mammalian-infective metacyclic forms. These parasites are unable to respond to nutrients to differentiate into proliferative retroleptomonads, which are required for their blood-meal induced amplification in sand flies and enhanced mammalian infectivity. We additionally show that RPTOR1-/- metacyclic promastigotes develop into amastigotes but do not proliferate in the mammalian host to cause pathology. RPTOR1-dependent TORC1 functionality represents a critical mechanism for driving parasite growth and proliferation.

KW - Animals

KW - Leishmania

KW - Psychodidae/parasitology

KW - Phlebotomus/parasitology

KW - Nutrients

KW - Cell Proliferation

KW - Mammals

U2 - 10.1038/s44319-024-00084-y

DO - 10.1038/s44319-024-00084-y

M3 - Article

C2 - 38396206

SN - 1469-221X

VL - 25

SP - 1075

EP - 1105

JO - EMBO Reports

JF - EMBO Reports

IS - 3

ER -