Evolution of protein trafficking in kinetoplastid parasites: Complexity and pathogenesis

Venkatesh, Divya; Zhang, Ning; Zoltner, Martin; Pino, Ricardo Canavate del; Field, Mark C.

doi:10.1111/tra.12601

Cited by 9 publications

(8 citation statements)

References 79 publications

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“…In T . brucei , regulation of protein trafficking is essential for surface expression and turnover of proteins such as VSGs and procyclins [ 89 ]. In T .…”

Section: Pi Kinases: Regulation Of Organelle Biogenesis and Traffickimentioning

confidence: 99%

The phosphoinositide regulatory network in Trypanosoma brucei: Implications for cell-wide regulation in eukaryotes

Cestari

Stuart

2020

PLoS Negl Trop Dis

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The unicellular eukaryote Trypanosoma brucei undergoes extensive cellular and developmental changes during its life cycle. These include regulation of mammalian stage surface antigen variation and surface composition changes between life stages; switching between glycolysis and oxidative phosphorylation; differential mRNA editing; and changes in posttranscriptional gene expression, protein trafficking, organellar function, and cell morphology. These diverse events are coordinated and controlled throughout parasite development, maintained in homeostasis at each life stage, and are essential for parasite survival in both the host and insect vector. Described herein are the enzymes and metabolites of the phosphatidylinositol (PI) cellular regulatory network, its integration with other cellular regulatory systems that collectively control and coordinate these numerous cellular processes, including cell development and differentiation and the many associated complex processes in multiple subcellular compartments. We conclude that this regulation is the product of the organization of these enzymes within the cellular architecture, their activities, metabolite fluxes, and responses to environmental changes via signal transduction and other processes. We describe a paradigm for how these enzymes and metabolites could function to control and coordinate multiple cellular functions. The significance of the PI system’s regulatory functions in single-celled eukaryotes to metazoans and their potential as chemotherapeutic targets are indicated.

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“…In T . brucei , regulation of protein trafficking is essential for surface expression and turnover of proteins such as VSGs and procyclins [ 89 ]. In T .…”

Section: Pi Kinases: Regulation Of Organelle Biogenesis and Traffickimentioning

confidence: 99%

The phosphoinositide regulatory network in Trypanosoma brucei: Implications for cell-wide regulation in eukaryotes

Cestari

Stuart

2020

PLoS Negl Trop Dis

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“…The importance of these molecules becomes evident when we consider their positive selection and their presence in a range of different trypanosomatid species. Homologs of GP63 ( Table 2 ) are found in the monoxenic trypanosomatids Paratrypanosoma and Crithidia ( Inverso et al, 1993 ; Cuevas et al, 2003 ; El-Sayed et al, 2005 ; Venkatesh et al, 2018 ) as well as in the free-living kinetoplastid Bodo saltans ( Jackson et al, 2016 ). The presence of GP63 is less enriched in B. saltans ( Table 2 ) than in trypanosomes, suggesting a possible change of function of this ancestral protease in parasites, which could be related to their survival inside the invertebrate host ( Jackson et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

The Glycosylphosphatidylinositol Anchor: A Linchpin for Cell Surface Versatility of Trypanosomatids

Borges

Link

Engstler

et al. 2021

Front. Cell Dev. Biol.

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The use of glycosylphosphatidylinositol (GPI) to anchor proteins to the cell surface is widespread among eukaryotes. The GPI-anchor is covalently attached to the C-terminus of a protein and mediates the protein’s attachment to the outer leaflet of the lipid bilayer. GPI-anchored proteins have a wide range of functions, including acting as receptors, transporters, and adhesion molecules. In unicellular eukaryotic parasites, abundantly expressed GPI-anchored proteins are major virulence factors, which support infection and survival within distinct host environments. While, for example, the variant surface glycoprotein (VSG) is the major component of the cell surface of the bloodstream form of African trypanosomes, procyclin is the most abundant protein of the procyclic form which is found in the invertebrate host, the tsetse fly vector. Trypanosoma cruzi, on the other hand, expresses a variety of GPI-anchored molecules on their cell surface, such as mucins, that interact with their hosts. The latter is also true for Leishmania, which use GPI anchors to display, amongst others, lipophosphoglycans on their surface. Clearly, GPI-anchoring is a common feature in trypanosomatids and the fact that it has been maintained throughout eukaryote evolution indicates its adaptive value. Here, we explore and discuss GPI anchors as universal evolutionary building blocks that support the great variety of surface molecules of trypanosomatids.

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“…Significantly, TbUsp7 knockdown decreased both ISG75 expression (~40%) and TbTpr86 (~58%) (Zoltner et al, 2015). The impact of TbSkpZ was highly biased towards surface/endosomal membrane proteins as well as proteins potentially associated with endocytosis, specifically VAMP7b SNARE (Tb927.5.3560) (Table 1, Figure 4) (Venkatesh et al, 2018). The Golgi complex localized Tb927.11.1750 gene product, present only in kinetoplastida, lacks an obvious TMD or GPI-anchor signal or structural homology using Rosetta and AlphaFold (data not shown) but was also decreased.…”

Section: Tbskpz Knockdown Inhibits Endocytosis and Reduces Tbusp7 And...mentioning

confidence: 99%

TUSK: a ubiquitin hydrolase complex modulating surface protein abundance in trypanosomes

et al. 2023

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Control of protein levels is vital to cellular homeostasis, for maintaining a steady state, to coordinate changes during differentiation and other roles. In African trypanosomes surface proteins contribute to immune evasion, drug sensitivity and environmental sensing. The trypanosome surface is dominated by the GPI-anchored variant surface glycoprotein, but additional GPI-anchored and trans-membrane domain proteins are present with known roles as nutrient receptors and signal transducers. The evolutionarily conserved deubiquitinase orthologs of Usp7 and Vdu1 in trypanosomes modulate abundance of many surface proteins, including the invariant surface glycoproteins, which have roles in immune evasion and drug sensitivity. Here we identify multiple trypanosome Skp1 paralogs and specifically a divergent paralog SkpZ. Affinity isolation and LCMSMS indicates that SkpZ forms a heterotrimeric complex with TbUsp7 and TbTpr86, a tetratricopeptide-repeat protein. Silencing SkpZ decreases TbUsp7 and TbTpr86 abundance, confirming a direct association. Further, SkpZ knockdown decreases the abundance of multiple trans-membrane domain (TMD) proteins but increases GPI-anchored surface protein levels. Hence, a heterotrimeric complex of TbTpr86, TbUsp7 and SkpZ (TUSK) regulates expression levels of a significant cohort of trypanosome surface proteins mediating coordination between TMD and GPI-anchored protein expression levels.

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Evolution of protein trafficking in kinetoplastid parasites: Complexity and pathogenesis

Cited by 9 publications

References 79 publications

The phosphoinositide regulatory network in Trypanosoma brucei: Implications for cell-wide regulation in eukaryotes

The phosphoinositide regulatory network in Trypanosoma brucei: Implications for cell-wide regulation in eukaryotes

The Glycosylphosphatidylinositol Anchor: A Linchpin for Cell Surface Versatility of Trypanosomatids

TUSK: a ubiquitin hydrolase complex modulating surface protein abundance in trypanosomes

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