Third target of rapamycin complex negatively regulates development of quiescence in
            <i>Trypanosoma brucei</i>

Barquilla, Antonio; Saldivia, Manuel; Díaz, Rafael Manuel Jiménez; Bart, Jean-Mathieu; Ferreirós-Vidal, Isabel; Calvo, Enrique; Hall, Michael N.; Navarro, Miguel

doi:10.1073/pnas.1210465109

Cited by 74 publications

(98 citation statements)

References 31 publications

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“…Proteins associated with FKBP12 have already been characterized in T. brucei, namely, TbTOR1, TbTOR2, TbTOR3, and TbTOR4 (43)(44)(45)(46)(47)(48). TOR, FKBP, and rapamycin are in a tripartite complex, therefore interfering with TOR or FKBP could lead to similar phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Trypanosoma brucei FKBP12 Differentially Controls Motility and Cytokinesis in Procyclic and Bloodstream Forms

et al. 2013

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e FKBP12 proteins are able to inhibit TOR kinases or calcineurin phosphatases upon binding of rapamycin or FK506 drugs, respectively. The Trypanosoma brucei FKBP12 homologue (TbFKBP12) was found to be a cytoskeleton-associated protein with specific localization in the flagellar pocket area of the bloodstream form. In the insect procyclic form, RNA interference-mediated knockdown of TbFKBP12 affected motility. In bloodstream cells, depletion of TbFKBP12 affected cytokinesis and cytoskeleton architecture. These last effects were associated with the presence of internal translucent cavities limited by an inside-out configuration of the normal cell surface, with a luminal variant surface glycoprotein coat lined up by microtubules. These cavities, which recreated the streamlined shape of the normal trypanosome cytoskeleton, might represent unsuccessful attempts for cell abscission. We propose that TbFKBP12 differentially affects stage-specific processes through association with the cytoskeleton.A frican trypanosomes are extracellular protozoan flagellated parasites responsible for sleeping sickness in humans and nagana in cattle. The life cycle of Trypanosoma brucei encompasses different stages, including the long slender bloodstream forms (BF) proliferating in mammalian blood and the procyclic forms (PF) that actively multiply in the gut of the Glossina vector (1).Trypanosomes are among the most divergent eukaryotes in evolution and display specific features, many of which are related to cell division probably due to the fact that most organelles are present at one copy per cell and have to be duplicated and segregated synchronously between the daughter cells. This division involves check points that differ from those of other eukaryotes, such as the control of karyokinesis when cytokinesis is inhibited (2, 3) and vice versa (4). Molecular effectors of these check points, such as mitogen-activated protein kinase and cyclin-dependent kinase, are present in trypanosomes but diverge in function compared to other eukaryotes (5, 6).The flagellum and its motility appear to play a key role in the control of cell division (7-9). This organelle initiates at the basal body, which is associated to the kinetoplast (10, 11), emerges from the flagellar pocket (FP), and it is attached along the cell body for most of its length by the flagellum attachment zone (FAZ). The flagellum contains a canonical axoneme and the paraflagellar rod (PFR) that are physically linked (12-14). The duplication and segregation of these structures are interdependent. During cytokinesis, the ingression of the cleavage furrow follows an axis in between the new and the old flagellum. The position and initiation of the furrow are closely related to the FAZ, as demonstrated by the study of flagellum mutants (15)(16)(17)(18)(19)(20)(21).In eukaryotes such as yeasts or mammals the TOR pathway is a major player in the control of cell division mediated by the action of two protein complexes, . These complexes contain the two different threonine/serine kinases T...

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Section: Discussionmentioning

confidence: 99%

“…TbTOR3 is a cytoplasmic TOR kinase involved in polyphosphate metabolism, acidocalcisome maintenance (46), and virulence (47). TbTOR4 is involved in differentiation of slender into stumpy bloodstream forms (48).…”

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confidence: 99%

Trypanosoma brucei FKBP12 Differentially Controls Motility and Cytokinesis in Procyclic and Bloodstream Forms

et al. 2013

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“…Studies have identified protein kinases that act as negative regulators in controlling parasite differentiation, such as the MAPK5, ZFK, and TbTOR4 kinases (Mony and Matthews, 2015). In addition, proteins associated with cAMP/AMP processing and purine balance may be involved, suggesting that the AMP/ATP ratio influences a finely tuned balance between energy consumption and differentiation processes (Barquilla et al, 2012; Laxman et al, 2006; Mony et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

“…In addition, a novel TOR kinase, TbTOR4, was identified that regulates the transition to quiescence in T. brucei . Ablation of TbTOR4 induces a molecular and biochemical phenotype that resembles the stumpy bloodstream form, which is pre-adapted to the insect host and to subsequent differentiation into the proliferative procyclic form (Barquilla et al, 2012). Conversely, TbTOR4 is significantly more phosphorylated in the procyclic form, suggesting that this kinase maintains the proliferation rate of the trypanosome and changes in response to nutritional requirements (Urbaniak et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The AMPKα1 Pathway Positively Regulates the Developmental Transition from Proliferation to Quiescence in Trypanosoma brucei

et al. 2016

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During infection in mammals, the protozoan parasite Trypanosoma brucei transforms from a proliferative bloodstream form to a quiescent form that is pre-adapted to host transition. AMP analogs are known to induce quiescence and also inhibit TbTOR4. To examine the role of AMP-activated kinase (AMPK) in regulation of this developmental transition, we characterized trypanosome TbAMPK complexes. Expression of a constitutively active AMPKα1 induces quiescence of the infective form and TbAMPKα1 phosphorylation occurs during differentiation of wild-type pleomorphic trypanosomes to the quiescent stumpy form in vivo. Compound C, a well-known AMPK inhibitor inhibits parasite differentiation in mice. We also provide evidence linking oxidative stress to TbAMPKα1 activation and quiescent differentiation, suggesting that TbAMPKα1 activation balances quiescence, proliferation and differentiation.

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“…It could be that a sub-population of slender forms (termed slender retainers by Mony and Matthews [4]) is refractory to SIF, or that local concentrations of SIF differ. Several regulators of SIF have been identified: the kinases MAPK5, ZFK and TOR4 [5][6][7] all make trypanosomes less receptive to the factor, while the RNA-binding protein RBP7, a MAP kinase kinase and several other proteins participate in stumpy formation and the progression to procyclic forms [4,8]. Thus, subtle differences in the balance between the pathways promoting maintenance as slender forms and progression to stumpy forms might determine the fate of a cell.…”

Section: Quorum Sensing and Differentiationmentioning

confidence: 99%

The languages of parasite communication

Roditi

2016

Molecular and Biochemical Parasitology

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Although it is regarded as self-evident that parasites interact with their hosts, with the primary aim of enhancing their own survival and transmission, the extent to which unicellular parasites communicate with each has been severely underestimated.Recent publications show that information is commonly exchanged between parasites of the same species and that this can govern their decisions to divide, to differentiate or to migrate as a group. Communication can take the form of soluble secreted factors, extracellular vesicles or contact between cells. Extracellular parasites can do this directly, while intracellular parasites use the infected host cell -or components derived from it -as an intermediary. By emitting signals that can be dispersed within the host, parasites can also have long-distance effects on the course of an infection and its pathology. This article presents an overview of recent developments in this field and draws attention to some older work that merits re-examination. 3 Most readers of this article will not need to be told that diseases such as sleeping sickness, malaria, Leishmaniasis, Trichomoniasis and Chagas Disease are caused by unicellular parasites. This knowledge might come with the tacit assumption that singlecelled organisms are completely self-sufficient and have no need to interact, much less cooperate, with members of their own species. In recent years, however, it has become apparent that a number of decisions are group decisions that rely on parasites communicating with each other. Just as animals can exchange information in different ways, be it vocally, visually, chemically or by body language, parasites have also developed a range of mechanisms for communicating with each other. This sometimes occurs directly, from parasite to parasite, or by using the infected host cell -or components derived from it -as an intermediary. By emitting signals that can be dispersed within the host, parasites can also have wide-ranging effects on the course of an infection and its pathology. This article presents an overview of recent developments in this field and draws attention to some older work that merits re-examination. Owing to space constraints, it will not cover molecules used by intracellular parasites to reprogram the cells that they infect. Quorum sensing and differentiationDifferent subspecies of Trypanosoma brucei, the pathogens responsible for human sleeping sickness and Nagana in domestic animals, are extracellular throughout their life cycle. In the mammalian host the parasites use a quorum sensing mechanism to maintain a balance between slender bloodstream forms, which are capable of dividing every 6-8 hours, and stumpy bloodstream forms, which cannot divide and have a lifespan of a few days. When trypanosomes ingested by a tsetse fly, the slender form is killed while the stumpy form survives and differentiates to the next life stage, the procyclic form, in the insect midgut [1,2]. If slender forms were to proliferate unchecked, this would result in rapid death of th...

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Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei

Cited by 74 publications

References 31 publications

Trypanosoma brucei FKBP12 Differentially Controls Motility and Cytokinesis in Procyclic and Bloodstream Forms

Trypanosoma brucei FKBP12 Differentially Controls Motility and Cytokinesis in Procyclic and Bloodstream Forms

The AMPKα1 Pathway Positively Regulates the Developmental Transition from Proliferation to Quiescence in Trypanosoma brucei

The languages of parasite communication

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