The trypanosome flagellar pocket

Field, Mark C.; Carrington, Mark

doi:10.1038/nrmicro2221

Cited by 235 publications

(262 citation statements)

References 110 publications

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“…3B), indicating that the mechanism blocking access of AQP2 to the plasma membrane is bloodstream-stage specific and developmentally regulated. The focal structure identified by the AQP2 signal in bloodstream-form cells is adjacent to the kinetoplast and may represent the flagellar pocket, an invagination of the pellicular membrane, which is inaccessible to host innate immune effectors and the exclusive site for endocytosis, exocytosis, and specific receptors (32). To test this hypothesis, we stained invariant surface glycoprotein 65 (ISG65), known to identify the flagellar pocket (33), and visualized both proteins by microscopy.…”

Section: Aqp2 Is Restricted To the Flagellar Pocket Specifically In Bmentioning

confidence: 99%

Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes

Baker

Glover

Munday

et al. 2012

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

138

262

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African trypanosomes cause sleeping sickness in humans, a disease that is typically fatal without chemotherapy. Unfortunately, drug resistance is common and melarsoprol-resistant trypanosomes often display cross-resistance to pentamidine. Although melarsoprol/pentamidine cross-resistance (MPXR) has been an area of intense interest for several decades, our understanding of the underlying mechanisms remains incomplete. Recently, a locus encoding two closely related aquaglyceroporins, AQP2 and AQP3, was linked to MPXR in a high-throughput loss-of-function screen. Here, we show that AQP2 has an unconventional "selectivity filter." AQP2-specific gene knockout generated MPXR trypanosomes but did not affect resistance to a lipophilic arsenical, whereas recombinant AQP2 reversed MPXR in cells lacking native AQP2 and AQP3. AQP2 was also shown to be disrupted in a laboratory-selected MPXR strain. Both AQP2 and AQP3 gained access to the surface plasma membrane in insect life-cycle-stage trypanosomes but, remarkably, AQP2 was specifically restricted to the flagellar pocket in the bloodstream stage. We conclude that the unconventional aquaglyceroporin, AQP2, renders cells sensitive to both melarsoprol and pentamidine and that loss of AQP2 function could explain cases of innate and acquired MPXR.

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Section: Aqp2 Is Restricted To the Flagellar Pocket Specifically In Bmentioning

confidence: 99%

Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes

Baker

Glover

Munday

et al. 2012

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

138

262

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“…T. brucei offers an attractive system in which to study this Rab protein on account of a streamlined endocytic system coupled to a high level of definition, together with extensive evidence that Rab orthologues maintain broadly similar functions across deep evolutionary time (Field and Carrington, 2009;Brighouse et al, 2010). T. brucei Rab28 (Tb927.6.3040) was initially identified by comprehensive screening of the trypanosome genome for Rasand Rab-like small GTPases (Berriman et al, 2005;Ackers et al, 2005); T. brucei Rab28 shares 49% identity and 58% similarity to H. sapiens RAB28 and extensive similarity to orthologues in other taxa, notably within the C-terminal hypervariable domain.…”

Section: T Brucei Rab28 Is a Novel Endocytic Proteinmentioning

confidence: 99%

“…T. brucei is experimentally tractable and a member of the Euglenozoa, a group suggested to be close to the eukaryotic evolutionary root, with a well-characterized endomembrane system (CavalierSmith, 2010;Field and Carrington, 2009). Trypanosomes have an ordered organellar anatomy with endocytosis and exocytosis restricted to an invagination of the plasma membrane, the flagellar pocket.…”

Section: Introductionmentioning

confidence: 99%

Rab28 function in trypanosomes: interactions with retromer and ESCRT pathways

Lumb

Leung

DuBois

et al. 2011

Journal of Cell Science

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SummaryEarly endosomal cargo is typically targeted to either a degradative or recycling pathway. Despite established functions for the retromer and ESCRT complexes at late endosomes/multivesicular bodies, the mechanisms integrating and coordinating these functions remain largely unknown. Rab family GTPases are key membrane trafficking organizers and could contribute. Here, in the unicellular organism Trypanosoma brucei, we demonstrate that Rab28 locates to the endosomal pathway and partially colocalizes with Vps23, an ESCRT I component. Rab28 is required for turnover of endocytosed proteins and for lysosomal delivery of protein cargo. Using RNA interference we find that in Rab28-depleted cells, protein levels of ESCRT I (Vps23/28) and retromer (Vps26) are also decreased, suggesting that Rab28 is an important regulator of these factors. We suggest that Rab28 coordinates the activity of retromer-dependent trafficking and ESCRT-mediated degradative pathways.

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“…Endocytosis is restricted to the flagellar pocket, a small specialized membrane structure at the posterior of the cell (8). This morphology requires that surface-associated proteins destined for endocytosis be laterally sorted in the plane of the membrane to the flagellar pocket.…”

mentioning

confidence: 99%

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

Harrington

Widener

Stephens

et al. 2010

Journal of Biological Chemistry

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Trypanosoma brucei is the causative agent of both a veterinary wasting disease and human African trypanosomiasis, or sleeping sickness. The cell membrane of the developmental stage found within the mammalian host, the bloodstream form (BSF), is highly dynamic, exhibiting rapid rates of endocytosis and lateral flow of glycosylphosphatidylinositol-anchored proteins. Here, we show that the cell membrane of these organisms is a target for killing by small hydrophobic peptides that increase the rigidity of lipid bilayers. Specifically, we have derived trypanocidal peptides that are based upon the hydrophobic N-terminal signal sequences of human apolipoproteins. These peptides selectively partitioned into the plasma membrane of BSF trypanosomes, resulting in an increase in the rigidity of the bilayer, dramatic changes in cell motility, and subsequent cell death. No killing of the developmental stage found within the insect midgut, the procyclic form, was observed. Additionally, the peptides exhibited no toxicity toward mammalian cell lines and did not induce hemolysis. Studies with model liposomes indicated that bilayer fluidity dictates the susceptibility of membranes to manipulation by hydrophobic peptides. We suggest that the composition of the BSF trypanosome cell membrane confers a high degree of fluidity and unique susceptibility to killing by hydrophobic peptides and is therefore a target for the development of trypanocidal drugs.

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The trypanosome flagellar pocket

Cited by 235 publications

References 110 publications

Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes

Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes

Rab28 function in trypanosomes: interactions with retromer and ESCRT pathways

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

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