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Article: Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death.

Candia, Robert F / Cohen, Leah S / Morozova, Viktoriya / Corbo, Christopher / Alonso, Alejandra D

2022 Volume 15, Page(s) 888420

Abstract: Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of ... ...

Abstract	Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of nuclear tau to the pathology of tauopathies. We have previously generated a pathological form of tau, PH-tau (pseudophosphorylation mutants S199E, T212E, T231E, and S262E) that mimics AD pathological behavior in cells,
Language	English
Publishing date	2022-05-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2022.888420
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Article ; Online: Methods to Investigate Signal Transduction Pathways in Trypanosoma cruzi: Cyclic Nucleotide Phosphodiesterases Assay Protocols.

Schoijet, Alejandra C / Sternlieb, Tamara / Alonso, Guillermo D

Methods in molecular biology (Clifton, N.J.)

2020 Volume 2116, Page(s) 523–534

Abstract: Intracellular levels of cyclic nucleotide second messengers are regulated predominantly by a large superfamily of phosphodiesterases (PDEs). Most of the different PDE variants play specific physiological functions; in fact, PDEs can associate with other ... ...

Abstract	Intracellular levels of cyclic nucleotide second messengers are regulated predominantly by a large superfamily of phosphodiesterases (PDEs). Most of the different PDE variants play specific physiological functions; in fact, PDEs can associate with other proteins allowing them to be strategically anchored throughout the cell. In this regard, precise cellular expression and compartmentalization of these enzymes produce the specific control of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) gradients in cells and enable their integration with other signaling pathways.In trypanosomatids, some PDEs are essential for their survival and play fundamental roles in the adaptation of these parasites to different environmental stresses, as well as in the differentiation between their different life cycle forms. Given that these enzymes not only are similar to human PDEs but also have differential biochemical properties, and due to the great knowledge of drugs that target human PDEs, trypanosomatid PDEs could be postulated as important therapeutic targets through the repositioning of drugs.In this chapter, we describe a simple and sensitive radioisotope-based method to measure cyclic 3',5'-nucleotide phosphodiesterase using [
MeSH term(s)	3',5'-Cyclic-AMP Phosphodiesterases/chemistry ; 3',5'-Cyclic-AMP Phosphodiesterases/isolation & purification ; 3',5'-Cyclic-AMP Phosphodiesterases/metabolism ; Cyclic AMP/chemistry ; Cyclic AMP/metabolism ; Enzyme Assays/methods ; Isotope Labeling/methods ; Life Cycle Stages ; Protozoan Proteins/chemistry ; Protozoan Proteins/isolation & purification ; Protozoan Proteins/metabolism ; Signal Transduction ; Tritium/chemistry ; Trypanosoma cruzi/metabolism
Chemical Substances	Protozoan Proteins ; Tritium (10028-17-8) ; Cyclic AMP (E0399OZS9N) ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17)
Language	English
Publishing date	2020-03-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-0294-2_31
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Article ; Online: Our Tau Tales from Normal to Pathological Behavior.

Alonso, Alejandra D / Cohen, Leah S

Journal of Alzheimer's disease : JAD

2018 Volume 64, Issue s1, Page(s) S507–S516

Abstract: The microtubule associated protein tau in a hyperphosphorylated form was identified as the building block of the filamentous aggregates found in the neurons of Alzheimer's disease (AD) patients. In the abnormal state, hyperphosphorylated tau from AD ... ...

Abstract	The microtubule associated protein tau in a hyperphosphorylated form was identified as the building block of the filamentous aggregates found in the neurons of Alzheimer's disease (AD) patients. In the abnormal state, hyperphosphorylated tau from AD brains (AD P-tau) was unable to promote microtubule assembly and more importantly, it could inhibit the normal activity of tau and other MAPs. AD P-tau was able to disrupt preformed microtubules and, by binding to normal tau, turn the latter into an AD P-tau like molecule. AD P-tau toxic behavior was prevalent in the soluble form and it was lost upon dephosphorylation. Mutations on tau associated with disease, e.g., R406W in frontotemporal dementia with Parkinsonism linked to chromosome 17, altered its conformation to make it a better substrate for kinases. Using phospho-mimetics, it was found that the minimum phospho-sites necessary to acquire such a toxic behavior of tau were at 199, 212, 231 and 262, and tau pseudophosphorylated at those sites in combination with R406W was named Pathological Human Tau (PH-Tau). PH-Tau expressed in cells had similar behavior to AD P-tau: disruption of the microtubule system, change in the normal subcellular localization, and gain of toxic function for cells. In animal models expressing PH-Tau, it was found that two putative mechanisms of neurodegeneration exist depending on the concentration of the toxic protein, both involving cognitive decline, due to synaptic dysfunction at lower concentration and neuronal death at higher. Studies investigating the mechanism of tau pathology and its transmission from neuron to neuron are currently ongoing.
MeSH term(s)	Animals ; Humans ; Neurons/metabolism ; Neurons/pathology ; Phosphorylation ; Tauopathies/metabolism ; Tauopathies/pathology ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2018-03-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-179906
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Article ; Online: Intracellular cyclic AMP levels modulate differential adaptive responses on epimastigotes and cell culture trypomastigotes of Trypanosoma cruzi.

Sternlieb, Tamara / Schoijet, Alejandra C / Alonso, Guillermo D

Acta tropica

2019 Volume 202, Page(s) 105273

Abstract: Among the many environmental challenges the parasite Trypanosoma cruzi has to overcome to complete its life cycle through different hosts, oxidative stress plays a central role. Different stages of this parasite encounter distinct sources of oxidative ... ...

Abstract	Among the many environmental challenges the parasite Trypanosoma cruzi has to overcome to complete its life cycle through different hosts, oxidative stress plays a central role. Different stages of this parasite encounter distinct sources of oxidative stress, such as the oxidative burst of the immune system, or the Heme released from hemoglobin degradation in the triatomine's midgut. Also, the redox status of the surroundings functions as a signal to the parasite, triggering processes coupled to differentiation or proliferation. Intracellular second messengers, like cAMP, are responsible for the transduction of environmental queues and initiating cellular processes accordingly. In trypanosomatids cAMP is involved in a variety of processes, including proliferation, differentiation, osmoregulation and quorum sensing. Trypanosomatid phosphodiesterases (PDE) show atypical pharmacological properties and some have been involved in key processes for the survival of the parasites, which validates them as attractive therapeutic targets. Our work here shows that cAMP modulates different processes according to parasite stage. Epimastigotes become more resistant to oxidative stress when pre-treated with cAMP analogs, while in trypomastigotes an increase in intracellular cAMP doesn't seem to aid in this response, although it does increase the number of amastigotes obtained 48 h after infection, compared to the control group. Also, we show that TcrPDEA1, a functionally enigmatic phosphodiesterase with very high Km, is involved in the epimastigotes response to oxidative stress.
MeSH term(s)	Animals ; Chlorocebus aethiops ; Cyclic AMP/metabolism ; Cytoplasm/metabolism ; Life Cycle Stages ; Oxidation-Reduction ; Trypanosoma cruzi/physiology ; Vero Cells
Chemical Substances	Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	2019-11-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	210415-5
ISSN	1873-6254 ; 0001-706X
ISSN (online)	1873-6254
ISSN	0001-706X
DOI	10.1016/j.actatropica.2019.105273
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Article ; Online: An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi.

Sternlieb, Tamara / Schoijet, Alejandra C / Genta, Patricio D / Vilchez Larrea, Salomé C / Alonso, Guillermo D

PLoS neglected tropical diseases

2021 Volume 15, Issue 5, Page(s) e0009435

Abstract: Trypanosoma cruzi, the etiological agent of Chagas disease, has a digenetic life cycle. In its passage from the insect vector to the mammalian host, and vice versa, it must be prepared to cope with abrupt changes in environmental conditions, such as ... ...

Abstract	Trypanosoma cruzi, the etiological agent of Chagas disease, has a digenetic life cycle. In its passage from the insect vector to the mammalian host, and vice versa, it must be prepared to cope with abrupt changes in environmental conditions, such as carbon source, pH, temperature and osmolarity, in order to survive. Sensing and signaling pathways that allow the parasite to adapt, have unique characteristics with respect to their hosts and other free-living organisms. Many of the canonical proteins involved in these transduction pathways have not yet been found in the genomes of these parasites because they present divergences either at the functional, structural and/or protein sequence level. All of this makes these pathways promising targets for therapeutic drugs. The AMP-activated protein kinase (AMPK) is a serine/threonine kinase activated by environmental stresses such as osmotic stress, hypoxia, ischaemia and exercise that results in reduction of ATP and increase of AMP levels. Thus, AMPK is regarded as a fuel gauge, functioning both as a nutrient and an energy sensor, to maintain energy homeostasis and, eventually, to protect cells from death by nutrient starvation. In the present study we report the characterization of AMPK complexes for the first time in T. cruzi and propose the function of TcAMPK as a novel regulator of nutritional stress in epimastigote forms. We show that there is phosphotransferase activity specific for SAMS peptide in epimastigotes extracts, which is inhibited by Compound C and is modulated by carbon source availability. In addition, TcAMPKα2 subunit has an unprecedented functional substitution (Ser x Thr) at the activation loop and its overexpression in epimastigotes led to higher autophagic activity during prolonged nutritional stress. Moreover, the over-expression of the catalytic subunits resulted in antagonistic phenotypes associated with proliferation. Together, these results point to a role of TcAMPK in autophagy and nutrient sensing, key processes for the survival of trypanosomatids and for its life cycle progression.
MeSH term(s)	AMP-Activated Protein Kinases/chemistry ; AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Autophagy ; Energy Metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Signal Transduction ; Stress, Physiological ; Trypanosoma cruzi/enzymology ; Trypanosoma cruzi/growth & development ; Trypanosoma cruzi/metabolism
Chemical Substances	Pyrazoles ; Pyrimidines ; dorsomorphin (10K52CIC1Z) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2021-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2727
ISSN (online)	1935-2735
ISSN	1935-2727
DOI	10.1371/journal.pntd.0009435
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Article: Intracellular cyclic AMP levels modulate differential adaptive responses on epimastigotes and cell culture trypomastigotes of Trypanosoma cruzi

Sternlieb, Tamara / Schoijet, Alejandra C / Alonso, Guillermo D

Acta tropica. 2020 Feb., v. 202

2020

Abstract	Among the many environmental challenges the parasite Trypanosoma cruzi has to overcome to complete its life cycle through different hosts, oxidative stress plays a central role. Different stages of this parasite encounter distinct sources of oxidative stress, such as the oxidative burst of the immune system, or the Heme released from hemoglobin degradation in the triatomine's midgut. Also, the redox status of the surroundings functions as a signal to the parasite, triggering processes coupled to differentiation or proliferation. Intracellular second messengers, like cAMP, are responsible for the transduction of environmental queues and initiating cellular processes accordingly. In trypanosomatids cAMP is involved in a variety of processes, including proliferation, differentiation, osmoregulation and quorum sensing. Trypanosomatid phosphodiesterases (PDE) show atypical pharmacological properties and some have been involved in key processes for the survival of the parasites, which validates them as attractive therapeutic targets. Our work here shows that cAMP modulates different processes according to parasite stage. Epimastigotes become more resistant to oxidative stress when pre-treated with cAMP analogs, while in trypomastigotes an increase in intracellular cAMP doesn't seem to aid in this response, although it does increase the number of amastigotes obtained 48 h after infection, compared to the control group. Also, we show that TcrPDEA1, a functionally enigmatic phosphodiesterase with very high Km, is involved in the epimastigotes response to oxidative stress.
Keywords	Triatominae ; Trypanosoma cruzi ; amastigotes ; cell culture ; cyclic AMP ; enzymes ; epimastigotes ; heme ; hemoglobin ; hosts ; immune system ; medicinal properties ; midgut ; osmoregulation ; oxidative stress ; parasites ; quorum sensing ; second messengers ; therapeutics ; trypomastigotes
Language	English
Dates of publication	2020-02
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	210415-5
ISSN	1873-6254 ; 0001-706X
ISSN (online)	1873-6254
ISSN	0001-706X
DOI	10.1016/j.actatropica.2019.105273
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Article ; Online: Homology Modeling and Molecular Dynamics Simulations of Trypanosoma cruzi Phosphodiesterase b1.

Llanos, Manuel A / Alberca, Lucas N / Larrea, Salomé C Vilchez / Schoijet, Alejandra C / Alonso, Guillermo D / Bellera, Carolina L / Gavenet, Luciana / Talevi, Alan

Chemistry & biodiversity

2021 Volume 19, Issue 1, Page(s) e202100712

Abstract: Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation and osmotic regulation of trypanosomatids; in some trypanosomatid species, they have been validated as molecular targets for the development of new ... ...

Abstract	Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation and osmotic regulation of trypanosomatids; in some trypanosomatid species, they have been validated as molecular targets for the development of new therapeutic agents. Because the experimental structure of Trypanosoma cruzi PDEb1 (TcrPDEb1) has not been solved so far, an homology model of the target was created using the structure of Trypanosoma brucei PDEb1 (TbrPDEb1) as a template. The model was refined by extensive enhanced sampling molecular dynamics simulations, and representative snapshots were extracted from the trajectory by combined clustering analysis. This structural ensemble was used to develop a structure-based docking model of the target. The docking accuracy of the model was validated by redocking and cross-docking experiments using all available crystal structures of TbrPDEb1, whereas the scoring accuracy was validated through a retrospective screen, using a carefully curated dataset of compounds assayed against TbrPDEb1 and/or TcrPDEb1. Considering the results from in silico validations, the model may be applied in prospective virtual screening campaigns to identify novel hits, as well as to guide the rational design of potent and selective inhibitors targeting this enzyme.
MeSH term(s)	3',5'-Cyclic-AMP Phosphodiesterases/chemistry ; 3',5'-Cyclic-AMP Phosphodiesterases/metabolism ; Amino Acid Sequence ; Area Under Curve ; Binding Sites ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Structure, Tertiary ; Protozoan Proteins/chemistry ; Protozoan Proteins/metabolism ; ROC Curve ; Sequence Alignment ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/metabolism ; Trypanosoma brucei brucei/enzymology ; Trypanosoma cruzi/enzymology
Chemical Substances	Protozoan Proteins ; Small Molecule Libraries ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17) ; PDEB1 protein, Trypanosoma brucei (EC 3.1.4.17)
Language	English
Publishing date	2021-12-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2139001-0
ISSN	1612-1880 ; 1612-1872
ISSN (online)	1612-1880
ISSN	1612-1872
DOI	10.1002/cbdv.202100712
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Article ; Online: The Phosphatidylinositol 3-kinase Class III Complex Containing TcVps15 and TcVps34 Participates in Autophagy in Trypanosoma cruzi.

Schoijet, Alejandra C / Sternlieb, Tamara / Alonso, Guillermo D

The Journal of eukaryotic microbiology

2017 Volume 64, Issue 3, Page(s) 308–321

Abstract: Autophagy is a degradative process by which eukaryotic cells digest their own components to provide aminoacids that may function as energy source under nutritional stress conditions. There is experimental evidence for autophagy in parasitic protists ... ...

Abstract	Autophagy is a degradative process by which eukaryotic cells digest their own components to provide aminoacids that may function as energy source under nutritional stress conditions. There is experimental evidence for autophagy in parasitic protists belonging to the family Trypanosomatidae. However, few proteins implicated in this process have been characterized so far in these parasites. Moreover, it has been shown that autophagy is involved in Trypanosoma cruzi differentiation and thus might have a role in pathogenicity. Here, we report the cloning and biochemical characterization of TcVps15. In addition, we demonstrate that TcVps15 interact with the PI3K TcVps34 and that both proteins associate with cellular membranes. Under nutritional stress conditions, TcVps15 and TcVps34 modify their subcellular distribution showing a partial co-localization in autophagosomes with TcAtg8.1 and using an active site TcVps15-mutated version (TcVps15-K219D-HA) we demonstrated that this relocalization depends on the TcVps15 catalytic activity. Overexpression of TcVps15-HA and TcVps15-K219D-HA also leads to increased accumulation of monodansylcadaverine (MDC) in autophagic vacuoles under nutritional stress conditions compared to wild-type cells. In addition, the MDC-specific activity shows to be significantly higher in TcVps15-HA overexpressing cells when compared with TcVps15-K219D-HA. Our results reveal for the first time a role of TcVps15 as a key regulator of TcVps34 enzymatic activity and implicate the TcVps15-Vps34 complex in autophagy in T. cruzi, exposing a new key pathway to explore novel chemotherapeutic targets.
MeSH term(s)	Animals ; Autophagy ; Cadaverine/analogs & derivatives ; Cadaverine/metabolism ; Cell Culture Techniques ; Cell Membrane/metabolism ; Class III Phosphatidylinositol 3-Kinases/genetics ; Class III Phosphatidylinositol 3-Kinases/metabolism ; Class III Phosphatidylinositol 3-Kinases/physiology ; Cloning, Molecular ; DNA, Protozoan ; Enzyme Assays ; Gene Expression Regulation, Enzymologic ; Life Cycle Stages ; Mutagenesis, Site-Directed ; Phagosomes/metabolism ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositol 3-Kinases/physiology ; Protozoan Proteins/biosynthesis ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism ; Sequence Analysis ; Transfection ; Trypanosoma cruzi/cytology ; Trypanosoma cruzi/enzymology ; Trypanosoma cruzi/genetics ; Trypanosoma cruzi/metabolism ; Two-Hybrid System Techniques ; Vacuolar Sorting Protein VPS15/genetics ; Vacuolar Sorting Protein VPS15/metabolism ; Vacuolar Sorting Protein VPS15/physiology ; Vacuoles/metabolism
Chemical Substances	DNA, Protozoan ; Protozoan Proteins ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Class III Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; Vacuolar Sorting Protein VPS15 (EC 2.7.11.1) ; monodansylcadaverine (I9N81SC5HD) ; Cadaverine (L90BEN6OLL)
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1147218-2
ISSN	1550-7408 ; 1066-5234
ISSN (online)	1550-7408
ISSN	1066-5234
DOI	10.1111/jeu.12367
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Article ; Online: An AMP-activated protein kinase complex with two distinctive alpha subunits is involved in nutritional stress responses in Trypanosoma cruzi.

Tamara Sternlieb / Alejandra C Schoijet / Patricio D Genta / Salomé C Vilchez Larrea / Guillermo D Alonso

PLoS Neglected Tropical Diseases, Vol 15, Iss 5, p e

2021 Volume 0009435

Abstract	Trypanosoma cruzi, the etiological agent of Chagas disease, has a digenetic life cycle. In its passage from the insect vector to the mammalian host, and vice versa, it must be prepared to cope with abrupt changes in environmental conditions, such as carbon source, pH, temperature and osmolarity, in order to survive. Sensing and signaling pathways that allow the parasite to adapt, have unique characteristics with respect to their hosts and other free-living organisms. Many of the canonical proteins involved in these transduction pathways have not yet been found in the genomes of these parasites because they present divergences either at the functional, structural and/or protein sequence level. All of this makes these pathways promising targets for therapeutic drugs. The AMP-activated protein kinase (AMPK) is a serine/threonine kinase activated by environmental stresses such as osmotic stress, hypoxia, ischaemia and exercise that results in reduction of ATP and increase of AMP levels. Thus, AMPK is regarded as a fuel gauge, functioning both as a nutrient and an energy sensor, to maintain energy homeostasis and, eventually, to protect cells from death by nutrient starvation. In the present study we report the characterization of AMPK complexes for the first time in T. cruzi and propose the function of TcAMPK as a novel regulator of nutritional stress in epimastigote forms. We show that there is phosphotransferase activity specific for SAMS peptide in epimastigotes extracts, which is inhibited by Compound C and is modulated by carbon source availability. In addition, TcAMPKα2 subunit has an unprecedented functional substitution (Ser x Thr) at the activation loop and its overexpression in epimastigotes led to higher autophagic activity during prolonged nutritional stress. Moreover, the over-expression of the catalytic subunits resulted in antagonistic phenotypes associated with proliferation. Together, these results point to a role of TcAMPK in autophagy and nutrient sensing, key processes for the survival of ...
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	572
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: The Phosphatidylinositol 3âkinase Class III Complex Containing TcVps15 and TcVps34 Participates in Autophagy in Trypanosoma cruzi

Schoijet, Alejandra C / Tamara Sternlieb / Guillermo D. Alonso

journal of eukaryotic microbiology. 2017 May, v. 64, no. 3

2017

Abstract	Autophagy is a degradative process by which eukaryotic cells digest their own components to provide aminoacids that may function as energy source under nutritional stress conditions. There is experimental evidence for autophagy in parasitic protists belonging to the family Trypanosomatidae. However, few proteins implicated in this process have been characterized so far in these parasites. Moreover, it has been shown that autophagy is involved in Trypanosoma cruzi differentiation and thus might have a role in pathogenicity. Here, we report the cloning and biochemical characterization of TcVps15. In addition, we demonstrate that TcVps15 interact with the PI3K TcVps34 and that both proteins associate with cellular membranes. Under nutritional stress conditions, TcVps15 and TcVps34 modify their subcellular distribution showing a partial coâlocalization in autophagosomes with TcAtg8.1 and using an active site TcVps15âmutated version (TcVps15âK219DâHA) we demonstrated that this relocalization depends on the TcVps15 catalytic activity. Overexpression of TcVps15âHA and TcVps15âK219DâHA also leads to increased accumulation of monodansylcadaverine (MDC) in autophagic vacuoles under nutritional stress conditions compared to wildâtype cells. In addition, the MDCâspecific activity shows to be significantly higher in TcVps15âHA overexpressing cells when compared with TcVps15âK219DâHA. Our results reveal for the first time a role of TcVps15 as a key regulator of TcVps34 enzymatic activity and implicate the TcVps15âVps34 complex in autophagy in T.Â cruzi, exposing a new key pathway to explore novel chemotherapeutic targets.
Keywords	Trypanosoma cruzi ; active sites ; amino acids ; autophagy ; catalytic activity ; cell membranes ; drug therapy ; energy ; enzyme activity ; eukaryotic cells ; malnutrition ; parasites ; pathogenicity ; phosphatidylinositol 3-kinase ; proteins ; protists ; vacuoles
Language	English
Dates of publication	2017-05
Size	p. 308-321.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	1147218-2
ISSN	1550-7408 ; 1066-5234
ISSN (online)	1550-7408
ISSN	1066-5234
DOI	10.1111/jeu.12367
Database	NAL-Catalogue (AGRICOLA)

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