A Leap Into the Unknown – Early Events in African Trypanosome Transmission

Szöőr, Balázs; Silvester, Eleanor; Matthews, Keith R.

doi:10.1016/j.pt.2019.12.011

Cited by 30 publications

(23 citation statements)

References 85 publications

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“…The transition of bloodstream to procyclic forms in vitro can be induced by different stimuli such as a drop in temperature, addition of citrate/cis-aconitate, mild acid, or proteases ( 25 , 73 , 74 , 75 , 76 ). Depleting BSF of glucose also induced this transition as well as upregulation of enzymes involved in proline metabolism ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

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Nutrient availability regulates proline/alanine transporters in Trypanosoma brucei

Haindrich

Ernst

Naguleswaran

et al. 2021

Journal of Biological Chemistry

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Trypanosoma brucei is a species of unicellular parasite that can cause severe diseases in livestock and humans, including African trypanosomiasis and Chagas disease. Adaptation to diverse environments and changes in nutritional conditions is essential for T. brucei to establish an infection when changing hosts or during invasion of different host tissues. One such adaptation is the ability of T. brucei to rapidly switch its energy metabolism from glucose metabolism in the mammalian blood to proline catabolism in the insect stages and vice versa. However, the mechanisms that support the parasite's response to nutrient availability remain unclear. Using RNAseq and qRT-PCR, we investigated the response of T. brucei to amino acid or glucose starvation and found increased mRNA levels of several amino acid transporters, including all genes of the amino acid transporter AAT7-B subgroup. Functional characterization revealed that AAT7-B members are plasma membrane-localized in T. brucei and when expressed in Saccharomyces cerevisiae supported the uptake of proline, alanine, and cysteine, while other amino acids were poorly recognized. All AAT7-B members showed a preference for proline, which is transported with high or low affinity. RNAi-mediated AAT7-B downregulation resulted in a reduction of intracellular proline concentrations and growth arrest under low proline availability in cultured procyclic form parasites. Taken together, these results suggest a role of AAT7-B transporters in the response of T. brucei to proline starvation and proline catabolism.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, addition of phloretin, an inhibitor, or glucose transporters causes at least partial differentiation of BSF to PCF ( 77 ). Glucose deprivation seems to be a rather slow adaptation and differentiation signal ( 76 ); nevertheless, it may be sufficient to induce AAT7-B expression.…”

Section: Discussionmentioning

confidence: 99%

Nutrient availability regulates proline/alanine transporters in Trypanosoma brucei

Haindrich

Ernst

Naguleswaran

et al. 2021

Journal of Biological Chemistry

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“…In a mammalian host, T. brucei multiplies extracellularly in the bloodstream and tissues as the bloodstream form (BF). At the peak of each wave of parasitemia, the dividing long-slender (LS) BF transforms into the non-dividing stumpy (ST) BF via a density-sensing phenomenon [128]. This non-dividing ST form ultimately perishes, and a new wave of the LS form appears with antigenically different surface proteins to evade the host's immune defense.…”

Section: The Role Of Tbtim50 In T Brucei Biologymentioning

confidence: 99%

“…PIP39 is a developmentally regulated protein in T. brucei. Its expression level is low in the replicating SL BF but high in the non-dividing ST BF and in the PF [128,133]. PIP39 is a substrate for phosphotyrosyl phosphatase (PTP).…”

Section: The Role Of Tbtim50 In T Brucei Biologymentioning

confidence: 99%

Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase

Chaudhuri

Tripathi

Gonzalez

2021

IJMS

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Mitochondria are essential in eukaryotes. Besides producing 80% of total cellular ATP, mitochondria are involved in various cellular functions such as apoptosis, inflammation, innate immunity, stress tolerance, and Ca2+ homeostasis. Mitochondria are also the site for many critical metabolic pathways and are integrated into the signaling network to maintain cellular homeostasis under stress. Mitochondria require hundreds of proteins to perform all these functions. Since the mitochondrial genome only encodes a handful of proteins, most mitochondrial proteins are imported from the cytosol via receptor/translocase complexes on the mitochondrial outer and inner membranes known as TOMs and TIMs. Many of the subunits of these protein complexes are essential for cell survival in model yeast and other unicellular eukaryotes. Defects in the mitochondrial import machineries are also associated with various metabolic, developmental, and neurodegenerative disorders in multicellular organisms. In addition to their canonical functions, these protein translocases also help maintain mitochondrial structure and dynamics, lipid metabolism, and stress response. This review focuses on the role of Tim50, the receptor component of one of the TIM complexes, in different cellular functions, with an emphasis on the Tim50 homologue in parasitic protozoan Trypanosoma brucei.

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“…The laboratory-adapted monomorphic strains loss their capacity to transform to ST BF. Upon treatment with AMP or AMP-analogues, it appears as a ST-like morphology (63). Interestingly, we noticed that TbTim50 KD changes the monomorphic LS BF to achieve ST-like appearance.…”

Section: Discussionmentioning

confidence: 76%

Trypanosoma bruceiTim50 Plays a Critical Role in Cell Cycle Regulation and Parasite Infectivity

Tripathi

Cooley

et al. 2021

Preprint

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Tim50 is a receptor subunit of the preprotein-translocase of the mitochondrial inner membrane, TIM23. Trypanosoma brucei, the infective agent for African trypanosomiasis, possesses a homologue of Tim50 (TbTim50) with a pair of characteristic DXDX(T/V) phosphatase signature motifs. Here, we demonstrated that besides its protein phosphatase activity, the recombinant TbTim50 binds and hydrolyzes phosphatidic acid in a concentration-dependent manner. In silico structural homology models identify the putative binding interfaces that may accommodate different phospho-substrates. Interestingly, TbTim50 depletion in the bloodstream form (BF) of T. brucei reduced cardiolipin (CL) levels and decreased mitochondrial membrane potential (ΔΨ). TbTim50 knockdown (KD) also reduced the population of G2 phase and increased G1 phase; thus, BF cell growth was reduced. Confocal and electron microscopy revealed a defect in regulation of kinetoplast (kDNA) replication due to TbTim50 KD. Depletion of TbTim50 increased the levels of AMPK phosphorylation, and parasite morphology was changed to stumpy-like with upregulation of few stumpy marker gene expressions. Importantly, we observed that TbTim50-depleted parasites were unable to establish infection in mice and rats. Proteomics analysis showed reductions of the translation factors, flagellar transport proteins, and many proteasomal subunits, including the mitochondrial HslVU that is known to play a role in kDNA replication. Reduction of the level of HslV in TbTim50 KD cells was further validated by immunoblot analysis. Altogether, our results showed that TbTim50 is essential for mitochondrial function, regulation of kDNA replication, and cell cycle in the BF. Therefore, TbTim50 is an important target for structure-based drug design to combat African trypanosomiasis.ImportanceAfrican trypanosomiasis, a neglected tropical disease caused by parasitic protozoan Trypanosoma brucei, is transmitted by the tsetse fly prevalent in sub-Saharan Africa. During its digenetic life cycle, T. brucei undergoes multiple developmental changes to adapt in different environments. T. brucei BF, dwelling in mammalian blood, generates ATP from glycolysis and hydrolyzes ATP in mitochondria for inner membrane potential. We found that TbTim50, a HAD-family phosphatase, is critical for T. brucei BF survival in vitro and in vivo. Depletion of TbTim50 in BF reduced CL levels and mitochondrial ΔΨ and caused a detrimental effect on many cellular functions. Cells accumulated in G1-S phase, and kinetoplast was over-replicated due to depletion of mitochondrial proteasomes, HslVU, a master-regulator of kDNA replication. Cell growth inhibition was accompanied by changes in morphology, AMPK phosphorylation, and upregulation of stumpy-specific gene expression. TbTim50 is essential for T. brucei survival and an important T. brucei therapeutic target.

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A Leap Into the Unknown – Early Events in African Trypanosome Transmission

Cited by 30 publications

References 85 publications

Nutrient availability regulates proline/alanine transporters in Trypanosoma brucei

Nutrient availability regulates proline/alanine transporters in Trypanosoma brucei

Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase

Trypanosoma bruceiTim50 Plays a Critical Role in Cell Cycle Regulation and Parasite Infectivity

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