A novel heterodimeric transferrin receptor encoded by a pair of VSG expression site-associated genes in T. brucei

Salmon, Didier; Geuskens, Maurice; Hanocq, Françoise; Hanocq-Quertier, J.; Nolan, Derek P.; Ruben, Larry; Pays, Étienne

doi:10.1016/0092-8674(94)90574-6

Cited by 166 publications

(183 citation statements)

References 28 publications

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“…Consequently, the evolutionary diversification of the VSG gene family has not been examined, although it has been suggested that VSG are a source of novel genes. Two gene families, the expression site-associated genes (ESAG6/7) encoding transferrin receptor (TFR) and the VSG-related (VR) genes, are thought to have evolved from a-VSG (17,18) and b-VSG (8,11), respectively.…”

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confidence: 99%

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Jackson

Berry

Aslett

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

145

206

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Antigenic variation enables pathogens to avoid the host immune response by continual switching of surface proteins. The protozoan blood parasite Trypanosoma brucei causes human African trypanosomiasis ("sleeping sickness") across sub-Saharan Africa and is a model system for antigenic variation, surviving by periodically replacing a monolayer of variant surface glycoproteins (VSG) that covers its cell surface. We compared the genome of Trypanosoma brucei with two closely related parasites Trypanosoma congolense and Trypanosoma vivax, to reveal how the variant antigen repertoire has evolved and how it might affect contemporary antigenic diversity. We reconstruct VSG diversification showing that Trypanosoma congolense uses variant antigens derived from multiple ancestral VSG lineages, whereas in Trypanosoma brucei VSG have recent origins, and ancestral gene lineages have been repeatedly coopted to novel functions. These historical differences are reflected in fundamental differences between species in the scale and mechanism of recombination. Using phylogenetic incompatibility as a metric for genetic exchange, we show that the frequency of recombination is comparable between Trypanosoma congolense and Trypanosoma brucei but is much lower in Trypanosoma vivax. Furthermore, in showing that the C-terminal domain of Trypanosoma brucei VSG plays a crucial role in facilitating exchange, we reveal substantial species differences in the mechanism of VSG diversification. Our results demonstrate how past VSG evolution indirectly determines the ability of contemporary parasites to generate novel variant antigens through recombination and suggest that the current model for antigenic variation in Trypanosoma brucei is only one means by which these parasites maintain chronic infections.

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mentioning

confidence: 99%

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Jackson

Berry

Aslett

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

145

206

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“…African trypanosomes cover their iron need by taking up host transferrin (Tf) (3)(4)(5). Uptake occurs in the flagellar pocket (3,6,7), an invagination of the plasma membrane where all endocytosis and traffic to the trypanosome surface takes place (8 -12), and is mediated by a transferrin receptor (Tf-R), a heterodimer consisting of subunits encoded by expression site-associated gene (ESAG) 6 and 7 (13)(14)(15)(16)(17), which are located in the telomeric VSG gene expression sites (for review, see Refs. 18 -21).…”

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confidence: 99%

Factors Affecting the Level and Localization of the Transferrin Receptor in Trypanosoma brucei

Mußmann

Engstler

Gerrits

et al. 2004

Journal of Biological Chemistry

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Transfer of bloodstream-form Trypanosoma brucei variant 221a from calf serum to dog serum-based medium induces acute iron starvation, as the transferrin receptor (Tf-R) of variant 221a binds dog Tf poorly. We show here that transfer to dog serum induces a 3-5-fold increase in Tf-R mRNA and protein within one doubling time (8 h). Because iron stores are still high 8 h after transfer, we infer that the signal for Tf-R overproduction is the decreased availability of cytosolic iron when cellular iron import drops. Up to 30% of the extra Tf-R spills out of the flagellar pocket onto the pellicular surface. Because the 5-fold increase in Tf-R is accompanied by a 5-fold increase in bovine Tf uptake, the up-regulation of Tf-R levels in response to Tf starvation helps the trypanosome to compete for limiting amounts of Tf. We noted that Tf-R levels also vary in calf serum medium. Cells in dense cultures contain up to 5-fold more Tf-R mRNA and protein than in dilute cultures. Only onetenth of the extra Tf-R reaches the pellicular surface. The increase cannot be explained by a lack of Tf or to cell density sensing but is due to pericellular hypoxia. Our results show that bloodstream-form trypanosomes can regulate the expression of the two Tf-R subunit genes and the localization of their gene products in a flexible manner. This flexibility is made possible by the promoter-proximal position of the two genes in the variant surface glycoprotein expression site.The unicellular protozoan parasite Trypanosoma brucei can infect a broad range of mammals. It multiplies extracellularly in blood and escapes elimination by the immune system through antigenic variation of its surface coat, which consists of one major protein species, the variant surface glycoprotein (VSG), 1 attached to the plasma membrane by a glycosylphosphatidylinositol anchor (1, 2). African trypanosomes cover their iron need by taking up host transferrin (Tf) (3-5). Uptake occurs in the flagellar pocket (3, 6, 7), an invagination of the plasma membrane where all endocytosis and traffic to the trypanosome surface takes place (8 -12), and is mediated by a transferrin receptor (Tf-R), a heterodimer consisting of subunits encoded by expression site-associated gene (ESAG) 6 and 7 (13-17), which are located in the telomeric VSG gene expression sites (for review, see .The ESAG6 subunit of about 400 amino acids is attached to the plasma membrane by a glycosylphosphatidylinositol anchor; ESAG7 of about 340 amino acids remains membraneattached by holding on to ESAG6 (for review, see Ref. 22). The trypanosomal Tf-R resembles VSG dimers in apparent structure and (distantly) in sequence (23), and it is unlike other Tf-Rs in nature.

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“…The trypanosome Tf-Rs are encoded by ESAG6 and ESAG7 and assemble as a heterodimeric receptor anchored to the flagellar pocket by a single GPI on the ESAG6-encoded subunit (6,27,54,63). The ESAG6 and ESAG7 subunits contain VSG-like N-terminal domains that facilitate packing within the VSG surface coat in the flagellar pocket and variable C-terminal sequences with differing affinities for mammalian transferrins (55).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei

et al. 2006

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A novel heterodimeric transferrin receptor encoded by a pair of VSG expression site-associated genes in T. brucei

Cited by 166 publications

References 28 publications

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

Factors Affecting the Level and Localization of the Transferrin Receptor in Trypanosoma brucei

In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei brucei

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