N-linked glycans containing linear poly-N-acetyllactosamine as sorting signals in endocytosis in Trypanosoma brucei

Nolan, Derek P.; Geuskens, Maurice; Pays, Étienne

doi:10.1016/s0960-9822(00)80018-4

Cited by 103 publications

(125 citation statements)

References 22 publications

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“…The TfR, like the lysosomal glycoprotein gp150͞CB1-gp (16) and the invariant surface glycoprotein ISG100 (17), binds to tomato lectin, suggesting the presence of linear poly-N-acetyllactosamine (-3Gal␤1-4GlcNAc␤1-) repeats (18). It has been postulated that these ␤-Gal-containing structures may be involved in retaining the TfR, and other recycling components, in the T. brucei flagellar pocket and the endosomal͞lysosomal membrane system (18).…”

Section: Discussionmentioning

confidence: 99%

“…It has been postulated that these ␤-Gal-containing structures may be involved in retaining the TfR, and other recycling components, in the T. brucei flagellar pocket and the endosomal͞lysosomal membrane system (18). In addition to the aforementioned glycoproteins, five other transmembrane glycoproteins, ISG65, ISG75 (19), the ecto-phosphatase AcP115 (20), the Golgi-and lysosome-associated glycoprotein tGLP-1 (21), and the Fla-1 glycoprotein (22), the latter associated with flagellar adhesion to the cell body (23), are known to be glycosylated, but the nature of their carbohydrate chains is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The few surviving cells failed to divide unless tetracycline was reintroduced at day 10 ( Fig. 5C) or until day [16][17][18][19][20], when the cultures spontaneously started to grow once more at normal rates (Fig. 5B).…”

Section: The T Brucei Gale Gene Is Essential To the Bloodstream Form Ofmentioning

confidence: 99%

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Galactose metabolism is essential for the African sleeping sickness parasite Trypanosoma brucei

Roper

Güther

Milne

et al. 2002

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

100

116

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The tsetse fly-transmitted protozoan parasite Trypanosoma brucei is the causative agent of human African sleeping sickness and the cattle disease Nagana. The bloodstream form of the parasite uses a dense cell-surface coat of variant surface glycoprotein to escape the innate and adaptive immune responses of the mammalian host and a highly glycosylated transferrin receptor to take up host transferrin, an essential growth factor. These glycoproteins, as well as other flagellar pocket, endosomal, and lysosomal glycoproteins, are known to contain galactose. The parasite is unable to take up galactose, suggesting that it may depend on the action of UDPglucose 4 -epimerase for the conversion of UDP-Glc to UDP-Gal and subsequent incorporation of galactose into glycoconjugates via UDP-Gal-dependent galactosyltransferases. In this paper, we describe the cloning of T. brucei galE, encoding T. brucei UDP-Glc-4 -epimerase, and functional characterization by complementation of a galE-deficient Escherichia coli mutant and enzymatic assay of recombinant protein. A tetracycline-inducible conditional galE null mutant of T. brucei was created using a transgenic parasite expressing the TETR tetracycline repressor protein gene. Withdrawal of tetracycline led to a cessation of cell division and substantial cell death, demonstrating that galactose metabolism in T. brucei proceeds via UDP-Glc-4 -epimerase and is essential for parasite growth. After several days without tetracycline, cultures spontaneously recovered. These cells were shown to have undergone a genetic rearrangement that deleted the TETR gene. The results show that enzymes and transporters involved in galactose metabolism may be considered as potential therapeutic targets against African trypanosomiasis.UDP-Gal ͉ galE ͉ epimerase T he tsetse fly-transmitted protozoan parasite Trypanosoma brucei causes human African sleeping sickness and the related cattle disease Nagana. There are 300,000-500,000 cases of the human disease per year in sub-Saharan Africa (1). The bloodstream form of the parasite divides by binary fission in the blood, lymph, and interstitial fluids of the mammalian host, and causes cachexia and anaemia in cattle and neurological disturbances in man. These conditions are fatal if not treated, and existing chemotherapies are toxic and difficult to administer. The need for new, less-toxic therapeutics is widely acknowledged (1).The bloodstream form of T. brucei is rich in galactosecontaining glycoproteins, most notably the variant surface glycoprotein (VSG) that, at 5 ϫ 10 6 homodimers per cell, forms a dense cell-surface coat. The VSG coat is a macromolecular diffusion barrier that protects the parasite from the innate immune system and also enables the parasite to undergo antigenic variation. Thus, although an individual parasite only expresses one VSG gene at a time, the parasite population can stay ahead of the host's specific immune response to expressed VSGs when a few parasites switch expression to one of several hundred genes encoding immunologically ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Galactose metabolism is essential for the African sleeping sickness parasite Trypanosoma brucei

Roper

Güther

Milne

et al. 2002

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

100

116

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“…TL binds tri-N-acetylglucosamine and specifically labels glycoproteins enriched in both the FP and endosomes of trypanosomes (21,22). This labeling revealed a clear bias in the localization toward particular sites (Fig.…”

mentioning

confidence: 91%

Membrane domains and flagellar pocket boundaries are influenced by the cytoskeleton in African trypanosomes

Gadelha

Rothery

Morphew

et al. 2009

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

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A key feature of immune evasion for African trypanosomes is the functional specialization of their surface membrane in an invagination known as the flagellar pocket (FP), the cell's sole site of endocytosis and exocytosis. The FP membrane is biochemically distinct yet continuous with those of the cell body and the flagellum. The structural features maintaining this individuality are not known, and we lack a clear understanding of how extracellular components gain access to the FP. Here, we have defined domains and boundaries on these surface membranes and identified their association with internal cytoskeletal features. The FP membrane appears largely homogeneous and uniformly involved in endocytosis. However, when endocytosis is blocked, receptor-mediated and fluid-phase endocytic markers accumulate specifically on membrane associated with four specialized microtubules in the FP region. These microtubules traverse a distinct boundary and associate with a channel that connects the FP lumen to the extracellular space, suggesting that the channel is the major transport route into the FP.electron tomography ͉ endocytosis ͉ freeze fracture ͉ Trypanosoma brucei ͉ flagellum P arasitic protozoa, like many cells, organize their surface membranes into subdomains or microenvironments that are specialized to accomplish particular recognition, secretory, and endocytic functions. The surfaces of parasitic organisms, however, have an extra level of constraint; they must perform these vital roles while the organism avoids elimination by defensive responses mounted by the host.The compartmentalization of surface membrane is especially interesting in African trypanosomes because of their particular parasitic lifestyle. Trypanosoma brucei is a flagellate protozoan that lives in the blood of mammals in an exclusively extracellular form, fully exposed to the host immune system. Survival is assisted both by rapid endocytosis that clears the entire cell surface of bound antibodies within Ϸ7 min (1) and through the expression of a series of immunologically distinct cell surface coats. Each coat is produced from a single GPI-anchored variant surface glycoprotein (VSG; ref.2). Periodic switching of the expressed VSG gene from a vast silent library enables the parasite to avoid clearance by the host's adaptive immune response, hence prolonging infection and increasing the chances of transmission by the bite of a tsetse fly.African trypanosomes maintain the VSG coat free of most invariant endocytosis receptors that could otherwise elicit an immune response from which the organism could not escape. This is achieved through specialization of the plasma membrane at the base of the flagellum to create a protected invagination, the flagellar pocket (FP), in which the invariant receptors for endocytosis and innate immune evasion are concentrated (3, 4). The FP is the sole site for all endocytosis and exocytosis, and along with this critical function, it also plays important roles in protein and lipid sorting and recycling (for review, see ref. ...

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“…ESAG1 and -2 are interesting candidates for the TLF receptor in T. b. brucei. ESAG2 is a GPI-anchored protein found exclusively in the flagellar pocket of bloodstream trypanosomes (40,44). Less is known about ESAG1, but it is predicted to be a transmembrane cell surface protein in bloodstream trypanosomes (44).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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N-linked glycans containing linear poly-N-acetyllactosamine as sorting signals in endocytosis in Trypanosoma brucei

Cited by 103 publications

References 22 publications

Galactose metabolism is essential for the African sleeping sickness parasite Trypanosoma brucei

Galactose metabolism is essential for the African sleeping sickness parasite Trypanosoma brucei

Membrane domains and flagellar pocket boundaries are influenced by the cytoskeleton in African trypanosomes

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

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