Ubiquitin and ubiquitin-like conjugation systems in trypanosomatids

Burge, Rebecca J; Mottram, Jeremy C.; Wilkinson, Anthony J.

doi:10.1016/j.mib.2022.102202

Cited by 6 publications

(1 citation statement)

References 53 publications

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“…Discoba likely represent an early branch following eukaryogenesis and hence valuable for illuminating processes following eukaryogenesis (Burki et al, 2020). Unsurprisingly, ubiquitylation in trypanosomes regulates the cell cycle and is essential for cellular homeostasis (Rojas et al, 2017, Hu et al, 2017, Benz and Clayton 2007, Damianou et al, 2020, Burge et al, 2022. Both the proteasome and ubiquitylation are involved in targeting and turnover of trypanosome surface proteins (Listovsky et al, 2011, Sharma et al, 2015, Chung, et al, 2008, Quintana et al, 2020, and a canonical ESCRT system functioning in late endocytic trafficking is present (Leung et al, 2008, Silverman et al, 2013, Venkatesh et al, 2018.…”

Section: Introductionmentioning

confidence: 99%

Evolution of cullin E3 ubiquitin ligases and function in trypanosomes

Pino¹,

Zoltner²,

Yamada³

et al. 2023

Preprint

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Post-translational modifications (PTMs) modulate protein function, with ubiquitylation a pre-eminent example with major roles in protein turnover. Ubiquitylation utilises a ligase enzyme cascade for conjugation of ubiquitin to client proteins and cullin-RING ligases are amongst the most complex known. We reconstructed evolution of cullin-RING E3 ubiquitin ligases across eukaryotes and experimentally characterised two cullin complexes in trypanosomatids, a taxon highly divergent from animals and fungi. We find considerable diversity within cullins and, in particular, trypanosomatids share only a minority of cullins with other lineages. Furthermore, we identify expansions in cullin client adaptor protein families, novel client adaptors and demonstrate client specificity. Finally we show that ornithine decarboxylase (TbODC), an important target of the drug trypanosome eflornithine, is a substrate for TbCul-A and overturn earlier models for eflornithine specificity. These studies highlight lineage-specific roles for cullin E3s and their contributions towards eukaryotic complexity.

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Section: Introductionmentioning

confidence: 99%

Evolution of cullin E3 ubiquitin ligases and function in trypanosomes

Pino¹,

Zoltner²,

Yamada³

et al. 2023

Preprint

View full text Add to dashboard Cite

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Formation of functional E3 ligase complexes with UBC2 and UEV1 of Leishmania mexicana

Burge,

Jameson,

Geoghegan

et al. 2024

Molecular and Biochemical Parasitology

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VPS28 regulates triglyceride synthesis and is mediated by the ubiquitination pathway in a bovine mammary epithelial cell line and mouse model

Liu,

Wang,

Zheng

et al. 2024

Preprint

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VPS28 (vacuolar protein sorting 28) is a subunit of the endosomal sorting complexes required for transport (ESCRTs), and is involved in ubiquitination. Ubiquitination is a crucial system for protein degradation in eukaryotes. Considering the recent findings on the role of ubiquitination in regulating lipid metabolism, we hypothesized that VPS28 might affect the expression of genes involved in milk fat synthesis. To test this hypothesis, we modulated VPS28 expression in the bovine mammary epithelial cell (MAC-T) line and measured the effects on triglyceride (TG) synthesis using lentivirus-mediated techniques. The results indicated that VPS28 knockdown significantly upregulated the fatty acid transporter CD36 (CD36 molecule) and the adipose differentiation-related protein (ADFP), leading to increased TG and fatty acid production, alongside elevated expression of ubiquitin (UB) protein and reduced proteasome activity. In contrast, VPS28 overexpression increased CD36 levels without significantly affecting ADFP and TG levels, showing a trend toward reduced lipid droplets and increased UB expression and proteasome activity. Furthermore, the inhibition of the ubiquitin-proteasome system and endosomal-lysosomal pathway using epoxomicin and chloroquine, respectively, resulted in a further elevation of CD36, ADFP, and TG levels, thereby enhancing cell viability. These in vitro findings were validated in vivo by a mouse model, where VPS28 knockdown enhanced CD36, ADFP, UB expression, TG content, and lipid droplets in mammary glands, without pathological changes in mammary tissue or blood TG alterations. These results confirm the pivotal role of VPS28 in regulating TG synthesis via the ubiquitination pathway, offering novel insights into the molecular mechanisms of milk fat production in a bovine in vitro cell model.

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Ubiquitin and ubiquitin-like conjugation systems in trypanosomatids

Cited by 6 publications

References 53 publications

Evolution of cullin E3 ubiquitin ligases and function in trypanosomes

Evolution of cullin E3 ubiquitin ligases and function in trypanosomes

Formation of functional E3 ligase complexes with UBC2 and UEV1 of Leishmania mexicana

VPS28 regulates triglyceride synthesis and is mediated by the ubiquitination pathway in a bovine mammary epithelial cell line and mouse model

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