ArticlePLoS pathogens2020
Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex.
Article in PLoS pathogens, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 37 citations in OpenAlex.
- Article
- Bi-directional highways and super-seeder tissues underpin parasite dissemination in experimental Leishmania donovani infection.Nature communications · 2026Article
- Five-layer systems analysis ofeLife · 2026Article
- A comprehensive review of CRISPR-Cas9-mediated genome editing in Leishmania strains: methodologies, applications, challenges and future directions.Molecular biology reports · 2026Review
- Eprinomectin InhibitsTransboundary and emerging diseases · 2026Article
- Article
- Glutamic acid-lysine (EK) rich motif of RabD2 self-associates and regulates adhesion through multivesicular bodies in Entamoeba histolytica.BMC biology · 2025Article
- Protein Profiling of Wild-CaughtPathogens (Basel, Switzerland) · 2025Article
- Structure and activity of the essential UCH family deubiquitinase DUB16 from Leishmania donovani.The Biochemical journal · 2025Article
- Article
- Determination of key hub genes in Leishmaniasis as potential factors in diagnosis and treatment based on a bioinformatics study.Scientific reports · 2024Article
- Siah2- and LRSAM1-mediated K63-linked ubiquitination of snakehead vesiculovirus nucleoprotein facilitates viral replication.Journal of virology · 2024Article
- Functional characterization of Cullin-1-RING ubiquitin ligase (CRL1) complex in Leishmania infantum.PLoS pathogens · 2024Article
- Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery.ACS bio & med chem Au · 2023Review
- In vitro Di-ubiquitin Formation Assay and E3 Cooperation Assay.Bio-protocol · 2022Article
- Antileishmanial metallodrugs and the elucidation of new drug targets linked to post-translational modifications machinery: pitfalls and progress.Memorias do Instituto Oswaldo Cruz · 2022Article
- Challenges and Tools for In VitroPathogens (Basel, Switzerland) · 2021Review
- Drug discovery in leishmaniasis using protein lipidation as a target.Biophysical reviews · 2021Review
- Deletion of Plasmodium falciparum ubc13 increases parasite sensitivity to the mutagen, methyl methanesulfonate and dihydroartemisinin.Scientific reports · 2021Article
- Systematic functional analysis of Leishmania protein kinases identifies regulators of differentiation or survival.Nature communications · 2021Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Post-translational modifications such as ubiquitination are important for orchestrating the cellular transformations that occur as the Leishmania parasite differentiates between its main morphological forms, the promastigote and amastigote. 2 E1 ubiquitin-activating (E1), 13 E2 ubiquitin-conjugating (E2), 79 E3 ubiquitin ligase (E3) and 20 deubiquitinating cysteine peptidase (DUB) genes can be identified in the Leishmania mexicana genome but, currently, little is known about the role of E1, E2 and E3 enzymes in this parasite. Bar-seq analysis of 23 E1, E2 and HECT/RBR E3 null mutants generated in promastigotes using CRISPR-Cas9 revealed numerous loss-of-fitness phenotypes in promastigote to amastigote differentiation and mammalian infection. The E2s UBC1/CDC34, UBC2 and UEV1 and the HECT E3 ligase HECT2 are required for the successful transformation from promastigote to amastigote and UBA1b, UBC9, UBC14, HECT7 and HECT11 are required for normal proliferation during mouse infection. Of all ubiquitination enzyme null mutants examined in the screen, Δubc2 and Δuev1 exhibited the most extreme loss-of-fitness during differentiation. Null mutants could not be generated for the E1 UBA1a or the E2s UBC3, UBC7, UBC12 and UBC13, suggesting these genes are essential in promastigotes. X-ray crystal structure analysis of UBC2 and UEV1, orthologues of human UBE2N and UBE2V1/UBE2V2 respectively, reveal a heterodimer with a highly conserved structure and interface. Furthermore, recombinant L. mexicana UBA1a can load ubiquitin onto UBC2, allowing UBC2-UEV1 to form K63-linked di-ubiquitin chains in vitro. Notably, UBC2 can cooperate in vitro with human E3s RNF8 and BIRC2 to form non-K63-linked polyubiquitin chains, showing that UBC2 can facilitate ubiquitination independent of UEV1, but association of UBC2 with UEV1 inhibits this ability. Our study demonstrates the dual essentiality of UBC2 and UEV1 in the differentiation and intracellular survival of L. mexicana and shows that the interaction between these two proteins is crucial for regulation of their ubiquitination activity and function.
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