Inositol phosphorylceramide synthase null Leishmania are viable and virulent in animal infections where salvage of host sphingomyelin predominates

Kuhlmann, F; Key, Phillip; Hickerson, Suzanne M.; Turk, John; Hsu, Fong‐Fu; Beverley, Stephen M.

doi:10.1016/j.jbc.2022.102522

Cited by 9 publications

(22 citation statements)

References 72 publications

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“…To confirm that sphingolipids do not shelter ergosterol in L. major , we used an L. major null mutant lacking the enzyme directly responsible for IPC synthesis from ceramide and phosphatidylinositol, ipcs — . Knockout of IPCS eliminates IPC but retains ceramide ( 12 ). To complement the knockout, episomal expression of IPCS in ipcs — cells ( ipcs − /+IPCS) was used ( 12 ).…”

Section: Resultsmentioning

confidence: 99%

“…Knockout of IPCS eliminates IPC but retains ceramide ( 12 ). To complement the knockout, episomal expression of IPCS in ipcs — cells ( ipcs − /+IPCS) was used ( 12 ). Similar to spt2 — , SLO ML and PFO ML binding of ipcs — was equivalent to wild type and ipcs − /+IPCS L. major ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1 , C and D ). Prior characterization of the ipcs — cells revealed an absence of IPC and accumulation of ceramide in the ipcs — cells, which was reverted by complementation ( 12 ). We conclude that neither ceramide (absent in spt2 — ) nor IPC (absent in both) alters ergosterol accessibility to CDCs in L. major .…”

Section: Resultsmentioning

confidence: 99%

“…Similar results are observed when SPT2 is chemically inhibited with the drug myriocin ( 7 ). Similarly, genetic deletion of IPCS completely depletes IPC without impacting parasite growth or virulence ( 12 ). These mutants retain upstream sphingolipids, including enhanced ceramide levels ( 12 ).…”

mentioning

confidence: 99%

“…Similarly, genetic deletion of IPCS completely depletes IPC without impacting parasite growth or virulence ( 12 ). These mutants retain upstream sphingolipids, including enhanced ceramide levels ( 12 ). Thus, both genetic and pharmacological tools exist to measure the control of Leishmania sphingolipids over ergosterol accessibility.…”

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confidence: 99%

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The sphingolipids ceramide and inositol phosphorylceramide protect the Leishmania major membrane from sterol-specific toxins

Haram¹,

Moitra²,

Keane³

et al. 2023

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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The sphingolipids ceramide and inositol phosphorylceramide protect the Leishmania major membrane from sterol-specific toxins

Haram¹,

Moitra²,

Keane³

et al. 2023

Journal of Biological Chemistry

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Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach

Alpizar-Sosa,

Zimbres,

Mantilla

et al. 2024

ACS Infect. Dis.

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The lack of effective vaccines and the development of resistance to the current treatments highlight the urgent need for new anti-leishmanials. Sphingolipid metabolism has been proposed as a promising source of Leishmania-specific targets as these lipids are key structural components of the eukaryotic plasma membrane and are involved in distinct cellular events. Inositol phosphorylceramide (IPC) is the primary sphingolipid in the Leishmania species and is the product of a reaction mediated by IPC synthase (IPCS). The antihistamine clemastine fumarate has been identified as an inhibitor of IPCS in L. major and a potent anti-leishmanial in vivo. Here we sought to further examine the target of this compound in the more tractable species L. mexicana, using an approach combining genomic, proteomic, metabolomic and lipidomic technologies, with molecular and biochemical studies. While the data demonstrated that the response to clemastine fumarate was largely conserved, unexpected disturbances beyond sphingolipid metabolism were identified. Furthermore, while deletion of the gene encoding LmxIPCS had little impact in vitro, it did influence clemastine fumarate efficacy and, importantly, in vivo pathogenicity. Together, these data demonstrate that clemastine does inhibit LmxIPCS and cause associated metabolic disturbances, but its primary target may lie elsewhere.

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Sphingolipids protect ergosterol in theLeishmania majormembrane from sterol-specific toxins

Haram

Moitra

Keane

et al. 2022

Preprint

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Nephrotoxicity is one common side effect of the first line anti-leishmanial treatment, liposomal amphotericin B. Amphotericin B targets ergosterol, so one approach to reducing dose and side effects could be improving the access of the drug to its target. While the surface exposure of ergosterol in Leishmania is unknown, sterols in mammalian cells can be sheltered from sterol-binding agents by membrane components, including sphingolipids. Here, we tested the ability of the Leishmania major sphingolipids inositol phosphorylceramide (IPC), and ceramide to shelter ergosterol by preventing binding and cytotoxicity of the sterol-binding toxins streptolysin O and perfringolysin O using flow cytometry. In contrast to mammalian systems, Leishmania sphingolipids did not preclude toxin binding to sterols in the membrane. However, IPC interfered with cytotoxicity. Ceramide reduced perfringolysin O, but not streptolysin O, cytotoxicity in cells. Ceramide sensing was controlled by the toxin L3 loop. Ceramide was sufficient to protect L. major promastigotes from amphotericin B. These findings suggest that L. major offers a genetically tractable model organism for understanding toxin-membrane interactions. Furthermore, our findings suggest targeting ceramide may enhance the efficacy of ergosterol-targeting anti-leishmanial drugs.

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Inositol phosphorylceramide synthase null Leishmania are viable and virulent in animal infections where salvage of host sphingomyelin predominates

Cited by 9 publications

References 72 publications

The sphingolipids ceramide and inositol phosphorylceramide protect the Leishmania major membrane from sterol-specific toxins

The sphingolipids ceramide and inositol phosphorylceramide protect the Leishmania major membrane from sterol-specific toxins

Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach

Sphingolipids protect ergosterol in theLeishmania majormembrane from sterol-specific toxins

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