ArticleProceedings of the National Academy of Sciences of the United States of America2009
Regulated expression of the Leishmania major surface virulence factor lipophosphoglycan using conditionally destabilized fusion proteins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 77 citations in OpenAlex.
- CRISPR-Cas13b mediated gene knockdowns in Leishmania infantum.International journal for parasitology. Drugs and drug resistance · 2025Article
- Next generation genetic screens in kinetoplastids.Nucleic acids research · 2025Review
- Ethanolaminephosphate cytidylyltransferase is essential for survival, lipid homeostasis and stress tolerance in Leishmania major.PLoS pathogens · 2023Article
- Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery.ACS bio & med chem Au · 2023Review
- Ethanolaminephosphate cytidyltransferase is essential for survival, lipid homeostasis and stress tolerance inbioRxiv : the preprint server for biology · 2023Article
- Article
- Quantitative single-cell analysis of Leishmania major amastigote differentiation demonstrates variably extended expression of the lipophosphoglycan (LPG) virulence factor in different host cell types.PLoS neglected tropical diseases · 2022Article
- A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice.NAR cancer · 2022Article
- Targeted protein degradation using deGradFP inWellcome open research · 2022Article
- Impact of Genetic Diversity and Genome Plasticity ofFrontiers in cellular and infection microbiology · 2022Review
- Catalase impairsVirulence · 2021Article
- Targeted protein degradation as a powerful research tool in basic biology and drug target discovery.Nature structural & molecular biology · 2020Review
- Tools for the Genetic Manipulation ofG3 (Bethesda, Md.) · 2020Article
- Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major.Molecular and biochemical parasitology · 2019Article
- Cyclopropane fatty acid synthesis affects cell shape and acid resistance in Leishmania mexicana.International journal for parasitology · 2018Article
- Countervailing, time-dependent effects on host autophagy promotes intracellular survival ofThe Journal of biological chemistry · 2018Article
- Direct and tunable modulation of protein levels in rice and wheat with a synthetic small molecule.Plant biotechnology journal · 2018Article
- Characterization of the Protein Tyrosine Phosphatase LmPRL-1 Secreted by Leishmania major via the Exosome Pathway.Infection and immunity · 2017Article
- A CRISPR Cas9 high-throughput genome editing toolkit for kinetoplastids.Royal Society open science · 2017Article
- Concomitant Immunity Induced by Persistent Leishmania major Does Not Preclude Secondary Re-Infection: Implications for Genetic Exchange, Diversity and Vaccination.PLoS neglected tropical diseases · 2016Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Surface glycoconjugates play important roles in the infectious cycle of Leishmania major, including the abundant lipophosphoglycan (LPG) implicated in parasite survival in the sand fly vector and the initial stages of establishment in the mammalian host macrophage. We describe a system for inducible expression of LPG, applying a novel protein-based system that allows controlled degradation of a key LPG biosynthetic enzyme, UDP-galactopyranose mutase (UGM). This methodology relies on a mutated FK506-binding protein (FKBP) destabilizing domain (dd) fused to the protein of interest; in the absence of rapamycin analogs, such as Shld1, the dd domain is destabilized, leading to proteasomal degradation, whereas drug treatment confers stabilization. Tests in L. major using dd fusions to a panel of reporters and cellular proteins confirmed its functionality, with a high degree of regulation and low background, and we established the kinetics of protein activation and/or loss. Two inexpensive and widely available ligands, FK506 and rapamycin, functioned similarly to Shld1, without effect on Leishmania growth or differentiation. We generated parasites lacking UGM through deletion of the GLF gene and substitution with a ddGLF fusion construct, either as chromosomal knockins or through episomal complementation; these showed little or no LPG expression in the absence of inducer, whereas in its presence, high levels of LPG were attained rapidly. Complement lysis tests confirmed the correct integrity of the Leishmania LPG coat. These data suggest that the dd approach has great promise in the study of LPG and other pathways relevant to parasite survival and virulence.
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