Trypanosoma brucei aquaglyceroporins mediate the transport of metabolic end-products: Methylglyoxal, D-lactate, L-lactate and acetate

Uzcátegui, Néstor L.; Figarella, Katherine; Segnini, Andrea; Marsiccobetre, Sabrina; Läng, Florian; Beitz, Eric; Rodrı́guez-Acosta, Alexis; Bertl, Adam

doi:10.1016/j.bbamem.2018.09.008

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…Tumor cells opt for relatively inefficient anaerobic glycolysis to generate abundant lactate even under oxygen-rich conditions. In T. brucei , BSFs rely heavily on glycolysis for ATP biosynthesis even under aerobic conditions, rather than tricarboxylic acid cycle and oxidative phosphorylation, whereas PCFs rely primarily on oxidative phosphorylation ( Bakker et al, 1997 ; Uzcátegui et al, 2018 ). During glycolysis, glucose consumed by cells is broken down to generate energy.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to other eukaryotes, trypanosomes compartmentalize their glycolytic enzymes in peroxisome-derived organelles known as glycosomes ( Bauer and Morris, 2017 ). Glycolysis generates several metabolic end-products that must be eliminated ( Uzcátegui et al, 2018 ). Lactate is abundantly produced during glycolysis in conventional eukaryotes ( Izzo and Wellen, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

Zhang

Jiang

et al. 2021

Front. Cell Dev. Biol.

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Lysine lactylation has been recognized as a novel post-translational modification occurring on histones. However, lactylation in non-histone proteins, especially in proteins of early branching organisms, is not well understood. Energy metabolism and the histone repertoire in the early diverging protozoan parasite Trypanosoma brucei, the causative agent of African trypanosomiasis, markedly diverge from those of conventional eukaryotes. Here, we present the first exhaustive proteome-wide investigation of lactylated sites in T. brucei. We identified 387 lysine-lactylated sites in 257 proteins of various cellular localizations and biological functions. Further, we revealed that glucose metabolism critically regulates protein lactylation in T. brucei although the parasite lacks lactate dehydrogenase. However, unlike mammals, increasing the glucose concentration reduced the level of lactate, and protein lactylation decreased in T. brucei via a unique lactate production pathway. In addition to providing a valuable resource, these foregoing data reveal the regulatory roles of protein lactylation of trypanosomes in energy metabolism and gene expression.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

Zhang

Jiang

et al. 2021

Front. Cell Dev. Biol.

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“…Tb AQP2 also presents a very different expression pattern compared to Tb AQP1 (the most abundant MIP in T. brucei ) and Tb AQP3 (only present in blood stages) 46 . Also, Tb AQP2 and Tb AQP3 have different subcellular localization and might play different roles in permeating water, glycerol and still undiscovered solutes 46 , 48 , 49 . Tb AQP2 changes in key residues plus the different localization and transcription levels among paralogs point to their neofunctionalization in the last common ancestor of T. brucei and T. evansi .…”

Section: Resultsmentioning

confidence: 99%

AQPX-cluster aquaporins and aquaglyceroporins are asymmetrically distributed in trypanosomes

et al. 2021

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Major Intrinsic Proteins (MIPs) are membrane channels that permeate water and other small solutes. Some trypanosomatid MIPs mediate the uptake of antiparasitic compounds, placing them as potential drug targets. However, a thorough study of the diversity of these channels is still missing. Here we place trypanosomatid channels in the sequence-function space of the large MIP superfamily through a sequence similarity network. This analysis exposes that trypanosomatid aquaporins integrate a distant cluster from the currently defined MIP families, here named aquaporin X (AQPX). Our phylogenetic analyses reveal that trypanosomatid MIPs distribute exclusively between aquaglyceroporin (GLP) and AQPX, being the AQPX family expanded in the Metakinetoplastina common ancestor before the origin of the parasitic order Trypanosomatida. Synteny analysis shows how African trypanosomes specifically lost AQPXs, whereas American trypanosomes specifically lost GLPs. AQPXs diverge from already described MIPs on crucial residues. Together, our results expose the diversity of trypanosomatid MIPs and will aid further functional, structural, and physiological research needed to face the potentiality of the AQPXs as gateways for trypanocidal drugs.

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“…Therefore, the CCCP inhibition of TbAQP2 must be seen as an unexpected and serious side effect that occurs at conventionally used concentrations. The different susceptibility of TbAQP2 and TbAQP3 for CCCP interaction is remarkable given their generally similar protein layout and electrostatic surface charge distribution [ 9 ]. Therefore, we relate the CCCP selectivity to the different selectivity filter layouts of TbAQP2 and TbAQP3 suggesting binding of CCCP in the peculiar ar/R region of TbAQP2 ( Figure 6 a).…”

Section: Discussionmentioning

confidence: 99%

“…TbAQP2 is a member of the solute channel subfamily of the ubiquitous homotetrameric aquaporins (AQP). It facilitates, besides water, the transmembrane passage of glycerol, urea, dihydroxyacetone [ 6 ], ammonia [ 7 ], arsenite and antimonite [ 8 ], lactic acid and methylglyoxal [ 9 ]. Although this substrate spectrum is common for aquaglyceroporins, the amino acid composition of the TbAQP2 selectivity filter is special [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

The Ionophores CCCP and Gramicidin but Not Nigericin Inhibit Trypanosoma brucei Aquaglyceroporins at Neutral pH

Petersen

Beitz

2020

Cells

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Human African trypanosomiasis (HAT) is caused by Trypanosoma brucei parasites. The T. brucei aquaglyceroporin isoform 2, TbAQP2, has been linked to the uptake of pentamidine. Negative membrane potentials and transmembrane pH gradients were suggested to promote transport of the dicationic antitrypanosomal drug. Application of ionophores to trypanosomes further hinted at direct inhibition of TbAQP2 by carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Here, we tested for direct effects of three classical ionophores (CCCP, nigericin, gramicidin) on the functionality of TbAQP2 and the related TbAQP3 at conditions that are independent from the membrane potential or a proton gradient. We expressed TbAQP2 and TbAQP3 in yeast, and determined permeability of uncharged glycerol at neutral pH using stopped-flow light scattering. The mobile proton carrier CCCP directly inhibited TbAQP2 glycerol permeability at an IC50 of 2 µM, and TbAQP3 to a much lesser extent (IC50 around 1 mM) likely due to different selectivity filter layouts. Nigericin, another mobile carrier, left both isoforms unaffected. The membrane-integral pore-forming gramicidin evenly inhibited TbAQP2 and TbAQP2 in the double-digit micromolar range. Our data exemplify the need for suitable controls to detect unwanted ionophore side effects even when used at concentrations that are typically recommended to disturb the transmembrane ion distribution.

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Trypanosoma brucei aquaglyceroporins mediate the transport of metabolic end-products: Methylglyoxal, D-lactate, L-lactate and acetate

Cited by 10 publications

References 40 publications

Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

AQPX-cluster aquaporins and aquaglyceroporins are asymmetrically distributed in trypanosomes

The Ionophores CCCP and Gramicidin but Not Nigericin Inhibit Trypanosoma brucei Aquaglyceroporins at Neutral pH

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