Release of Ecto-protein Kinases by the Protozoan ParasiteLeishmania major

Sacerdoti‐Sierra, Nina; Jaffe, Charles L.

doi:10.1074/jbc.272.49.30760

Cited by 47 publications

(36 citation statements)

References 26 publications

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“…56)), not only use ATP as phosphoryl donor but also other NTPs. Because several described ecto-protein kinases display characteristics of a protein kinase CK2 (20,24,57), we studied the specificity of the GPEET kinase for NTPs by adding excess amounts of non-radioactive ATP, CTP, GTP, or UTP to procyclic membranes incubated in the presence of [␥-32 P]ATP (Fig. 4).…”

Section: Resultsmentioning

confidence: 99%

“…Cell membrane-associated and secreted kinases have been shown to phosphorylate parasite or host proteins in Trichinella spiralis infective larvae (14,15), Toxoplasma gondii tachyzoites (16), and Leishmania spp. promastigotes (17)(18)(19)(20)(21). It has been speculated that the ecto-protein kinases from Leishmania may be involved in modulating the host immune system or host-parasite interactions.…”

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confidence: 99%

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Coordinate Expression of GPEET Procyclin and Its Membrane-associated Kinase in Trypanosoma brucei Procyclic Forms

Schlaeppi

Malherbe

Bütikofer

2003

Journal of Biological Chemistry

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GPEET procyclin is a major glycosylphosphatidylinositol-anchored protein of procyclic (insect stage) trypanosomes in culture and is heavily phosphorylated in the GPEET pentapeptide repeat. The phosphorylation reaction is a late event and occurs during maturation and transport of GPEET or on the parasite surface by an ecto-protein kinase. Initial biochemical characterization of the GPEET kinase activity now shows that it depends on bivalent cations for maximal activity, is stimulated by sulfhydryl group reagents, and is specific for ATP as phosphoryl donor. No kinase activity is detected in bloodstream form trypanosomes in culture, whereas strong phosphorylation is observed in early procyclic forms. In addition, the GPEET kinase activity is absent from procyclic trypanosomes that have repressed GPEET synthesis but can be induced in these same stocks by conditions, which also induce GPEET expression. However, the presence of an active kinase does not depend on the presence of (functional) GPEET because it can be detected in parasites expressing a non-phosphorylatable GPEET mutant protein and in procyclin null mutant trypanosomes. Interestingly, the presence of the glycosylphosphatidylinositol lipid moiety seems necessary for GPEET to become phosphorylated. Together, the results demonstrate that GPEET and its kinase are expressed during the same life cycle stages and that factors that induce the expression of GPEET in vitro also induce the expression of the GPEET kinase.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Coordinate Expression of GPEET Procyclin and Its Membrane-associated Kinase in Trypanosoma brucei Procyclic Forms

Schlaeppi

Malherbe

Bütikofer

2003

Journal of Biological Chemistry

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“…A total of 50 ϫ 10 6 confluent L. major promastigotes were washed with buffer A (20 mM Tris-HCl, pH 7.4, 150 mM NaCl, 10 mM MgCl 2 , 1 mM glucose, and 10 mM NaF). Cells were then resuspended in buffer A containing 50 g/ml of GST-IFNAR1 at 30°C for 20 min as described previously (47). The supernatant was collected, supplemented with 2 mM of ATP, and further incubated at 30°C for 15 min.…”

Section: Ifnar1mentioning

confidence: 99%

“…Within this cycle, Leishmania promastigotes are released from the insect gut to invade macrophages and dendritic cells in the mammalian hosts via phagocytosis to become mammal-parasitizing amastigotes (reviewed in reference 41). Intriguingly, there are reports that various species of Leishmania are capable of secreting the CK1-like kinase that is active against several host mammalian substrates, including membrane proteins (47,58). We have used the reported experimental conditions to test whether such activity is capable of phosphorylating IFNAR1.…”

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confidence: 99%

Mammalian Casein Kinase 1α and Its Leishmanial Ortholog Regulate Stability of IFNAR1 and Type I Interferon Signaling

Liu¹,

Carvalho

Bhattacharya³

et al. 2009

Molecular and Cellular Biology

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Phosphorylation of the degron of the IFNAR1 chain of the type I interferon (IFN) receptor triggers ubiquitination and degradation of this receptor and, therefore, plays a crucial role in negative regulation of IFN-␣/␤ signaling. Besides the IFN-stimulated and Jak activity-dependent pathways, a basal ligand-independent phosphorylation of IFNAR1 has been described and implicated in downregulating IFNAR1 in response to virus-induced endoplasmic reticulum (ER) stress. Here we report purification and characterization of casein kinase 1␣ (CK1␣) as a bona fide major IFNAR1 kinase that confers basal turnover of IFNAR1 and cooperates with ER stress stimuli to mediate phosphorylation-dependent degradation of IFNAR1. Activity of CK1␣ was required for phosphorylation and downregulation of IFNAR1 in response to ER stress and viral infection. While many forms of CK1 were capable of phosphorylating IFNAR1 in vitro, human CK1␣ and L-CK1 produced by the protozoan Leishmania major were also capable of increasing IFNAR1 degron phosphorylation in cells. Expression of leishmania CK1 in mammalian cells stimulated the phosphorylation-dependent downregulation of IFNAR1 and attenuated its signaling. Infection of mammalian cells with L. major modestly decreased IFNAR1 levels and attenuated cellular responses to IFN-␣ in vitro. We propose a role for mammalian and parasite CK1 enzymes in regulating IFNAR1 stability and type I IFN signaling.Cytokines that belong to a superfamily of interferons (IFNs), including type I IFN (such as IFN-␤ and numerous species of IFN-␣) and type II interferon (IFN-␥), are important for efficient antiviral defense (40, 51). Type I IFNs signal via interacting with the heterodimeric receptor complex composed of two chains (IFNAR1 and IFNAR2); ligand binding activates receptor-associated members of the JAK family of tyrosine kinases, Jak1 and Tyk2. These kinases phosphorylate and activate the signal transducers and activators of transcription (STAT) proteins, which increase transcription of the IFN-induced genes whose products exert antiviral, immunomodulatory, and antiproliferative effects. While some of the IFN actions might proceed in a STAT-independent manner, all biological functions of IFN-␣/␤ reported to date rely on the function of the type I IFN receptor complex (reviewed in references 1, 54, and 55).The IFNAR1 subunit of this receptor is essential for IFN-␣/␤ signaling. Mice lacking IFNAR1 display a deficiency in antiviral responses (24,36) and an altered immune activation in response to a number of microbial agents (57). Intriguingly, these mice do not display an increased susceptibility to a number of protozoans, including Leishmania spp. (57), which is lethal in animals that lack responses to IFN-␥ (50). However, similar to IFN-␥, IFN-␣ also activates STAT1 and upregulates the inducible nitric oxide synthase, which is essential in the early defense against Leishmania (5), which by itself stimulates the production of type I IFN during the early infection stage (14).In wild-type animals, the levels of I...

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“…This flagellar pocket domain may take part in the vesicle docking during exocytosis [316]. The uptake of several macromolecules was described in promastigotes and amastigotes both in axenic and inside macrophages [45,68,261,278]. Interestingly both promastigotes and amastigotes are able to exchange membrane components with host cells in a dynamic and developmentally regulated process [136].…”

Section: Ultrastructure and Biologymentioning

confidence: 98%

Leishmania-Host Interplay: The Everlasting Rivalry

Martiny¹,

Vannier-Santos²

2005

MCRO

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Parasitic protozoa of the genus Leishmania infect mammalian mononuclear phagocytic cells causing a potentially fatal disease with a broad spectrum of clinical manifestations. The drugs of choice used in the leishmaniasis therapy are significantly toxic, expensive and faced with a growing frequency of refractory infections. Thus the search for new leishmanicidal compounds is urgently required. In order to perform a proper drug design and to understand the modes of action of such compounds it is necessary to elucidade the intrincate cellular and molecular events that orchestrate the parasite biology. To invade host cells Leishmania recruit different surface receptors that may assist engaging the microbicidal responses. Even before gaining the intracellular millieu these pathogens can deactivate and/or subvert the phagocyte signal transduction machinery rendering these cells permissive to infection. In the present review we attempted to approach some of the most relevant cellular and biochemical invasion strategies employed by Leishmania parasites.

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Release of Ecto-protein Kinases by the Protozoan ParasiteLeishmania major

Cited by 47 publications

References 26 publications

Coordinate Expression of GPEET Procyclin and Its Membrane-associated Kinase in Trypanosoma brucei Procyclic Forms

Coordinate Expression of GPEET Procyclin and Its Membrane-associated Kinase in Trypanosoma brucei Procyclic Forms

Mammalian Casein Kinase 1α and Its Leishmanial Ortholog Regulate Stability of IFNAR1 and Type I Interferon Signaling

Leishmania-Host Interplay: The Everlasting Rivalry

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