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Five-layer systems analysis of Leishmania stage differentiation reveals an essential role for protein degradation in parasite development

ABSTRACT: Leishmania survival and pathogenicity depends on the parasite’s capacity to adapt to different host environments through stage differentiation of promastigotes within the sand fly, and of amastigotes inside mammalian host cells. Leishmania stage-specific expression occurs in the absence of classical transcriptional regulation, raising the question on alternative regulatory mechanisms. We investigated the role of protein turnover by applying label-free quantitative proteomic on both L. donovani amastigotes purified from the spleen of infected hamsters and the derived promastigotes in presence or absence of the irreversible, proteasomal inhibitor lactacystin. Proteins were prepared from four replicates for each condition.

INSTRUMENT(S):

ORGANISM(S): Leishmania Donovani

TISSUE(S): Spleen, Cell Line Cell

DISEASE(S): Leishmaniasis

SUBMITTER: Thibaut Douché

LAB HEAD: Gerald, F, Spath

PROVIDER: PXD035698 | Pride | 2026-06-15

REPOSITORIES: Pride

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			Action	DRS
	20180911_Q2_TD_ColQ2-44_Pescher-Lacta_H208-2_P2_lacta.raw	Raw
	20180911_Q2_TD_ColQ2-44_Pescher-Lacta_H208-2_ama_0-18H.raw	Raw
	20180911_Q2_TD_ColQ2-44_Pescher-Lacta_H208-2_ama_T0.raw	Raw
	20180911_Q2_TD_ColQ2-44_Pescher-Lacta_H208-2_ama_lacta.raw	Raw
	20180911_Q2_TD_ColQ2-44_Pescher-Lacta_H208-2_p2_0-18H.raw	Raw

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Project description:Protozoa of the genus Leishmania are the causative agents of leishmaniasis in humans. These parasites cycle between promastigotes in the sand fly mid-gut and amastigotes in phagolysosome of mammalian macrophages. During infection, host up-regulate nitric oxide synthase and parasite induce host arginase expression, both of which use arginine as a substrate. These elevated activities deplete macrophage arginine pools, a situation that invading Leishmania must overcome since it is an essential amino acid. Leishmania donovani imports exogenous arginine via a mono-specific amino acid transporter (AAP3) and utilizes it primarily through the polyamine pathway to provide precursors for trypanothione biosynthesis. Here we report the discovery of a pathway whereby promastigote and amastigote forms of the Leishmania sense the lack of environmental arginine and respond with rapid up-regulation in AAP3 expression and activity, as well as several other transporters. Significantly, this arginine deprivation response is also activated in parasites during macrophage infection. Phosphoproteomic analyses of L. donovani promastigotes have implicated a Mitogen-Activated Protein Kinase 2 (MPK2)-mediated signaling cascade in this response and L. mexicana mutants lacking MPK2 are unable to respond to arginine deprivation. In this study, we established that Leishmania cells sense the absence of arginine in their environment; both in culture (axenic promastigotes and amastigotes) and in macrophages during infection (amastigotes). This study describes the first amino acid deprivation sensing mechanism and the pathway that transduce this response, and reveals a novel host-pathogen metabolic interplay. Total RNA from Ten Leishmania donovani samples were analyzed using RNA-Seq. Cells from two life stages (promastigotes and amastigotes) were grown in axenic culture in the presence and absense of arginine. For each condition two biological replicates were grown and analyzed. In addition two macrophage grown amastigotes were analyzed.

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Five-layer systems analysis of Leishmania stage differentiation reveals an essential role for protein degradation in parasite development

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