γ-glutamyl transpeptidase, an ecto-enzyme regulator of intracellular redox potential, is a component of TM4 signal transduction complexes

Nichols, Timothy C.; Guthridge, Joel M.; Karp, David R.; Molina, Hector; Fletcher, Dana R.; Holers, V. Michael

doi:10.1002/(sici)1521-4141(199812)28:12<4123::aid-immu4123>3.0.co;2-g

Cited by 56 publications

(31 citation statements)

References 15 publications

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“…CD63 and other tetraspanins can be coimmunoprecipitated with type II phosophoinositide 4-kinase (39,40) and ␥-glutamyl transpeptidase (41). The presence of these enzymes suggests that their recruitment to specific tetraspanin-rich areas of membranes may mediate regulated signaling events.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of CD63 toCryptococcus neoformansphagosomes requires acidification

Artavanis‐Tsakonas

Love

Ploegh

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The subcellular localization of the cluster of differentiation 63 (CD63) tetraspanin and its interaction with the class II MHC antigen presentation pathway were examined in the context of phagocytosis by live cell imaging, by using monomeric red fluorescent protein-tagged mouse CD63 expressed in primary bone marrow-derived cell cultures. Upon phagocytosis of Cryptococcus neoformans and polystyrene beads, CD63 was recruited selectively to C. neoformans-containing phagosomes in a MyD88-independent acidification-dependent manner. Bead-containing phagosomes, within a C. neoformans-containing cell, acidified to a lesser extent and failed to recruit CD63 to a level detectable by microscopy. CD63 recruitment to yeast phagosomes occurred independently of class II MHC and LAMP-1. These observations indicate that the composition of distinct phagosomal compartments within the same cell is determined by phagosomal cargo and may affect the outcome of antigen processing and presentation.dendritic cells ͉ live cell imaging ͉ lysosome ͉ phagocytosis ͉ yeast P rofessional antigen-presenting cells (APCs) acquire microbial pathogens by phagocytosis and process them for presentationbyclassIIMHCmolecules.Internalizationofparticulate matter can be mediated through a number of receptors, including Fc receptors, complement receptors, integrins, and scavenger receptors. Each mode of entry is associated with specific morphological changes, all of which ultimately result in formation of the phagosome (reviewed in ref. 1). Phagosome maturation is complex and not completely understood. Once formed, the phagosome undergoes a series of fusion and fission events that sequentially incorporate elements of early endosomes, late endosomes, and lysosomes; these events result in dynamic delivery and removal of material (reviewed in ref. 2).Several pathogens successfully evade immune attack by exploiting the phagosomal environment to render it favorable for replication and survival. Examples include Leishmania donovani (3), Salmonella typhimurium (4), Mycobacterium tuberculosis (5), and Cryptococcus neoformans (6). Furthermore, internalization of different pathogenic organisms may yield functionally distinct phagosomes. Whatever the routes involved in pathogen entry and subsequent phagosome maturation, current models would benefit from a more accurate description of phagocytosis in living cells through use of suitably tagged endosomal proteins, such as the class II MHC products that ultimately present pathogen-derived peptides (7).Here we investigate the cluster of differentiation 63 (CD63) tetraspanin within the endosomal pathway by tagging it with monomeric red fluorescent protein (mRFP1) and using live cell imaging to observe its behavior in primary mouse APCs. CD63, also known as LAMP-3, was characterized originally as a platelet activation marker (8) and has been used as a marker of late endosomes and lysosomes (9). More recently, the focus has shifted to its interaction with class II MHC and its role in antigen presentation. In professional APC...

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Section: Discussionmentioning

confidence: 99%

Recruitment of CD63 toCryptococcus neoformansphagosomes requires acidification

Artavanis‐Tsakonas

Love

Ploegh

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…With regard to the second possibility, that hCR2 alters homotypic adhesion, previous studies have shown that engagement of CR2 promotes homotypic adhesion of B cell lines (29,52), most likely in a CD19/CD81-dependent manner. Based on these findings, and the postulated importance of B cell:B cell homotypic interactions during bone marrow development (2), it is possible that the binding of ligand to hCR2 could alter this process in a detrimental manner.…”

Section: Discussionmentioning

confidence: 99%

Expression of Human Complement Receptor Type 2 (CD21) in Mice During Early B Cell Development Results in a Reduction in Mature B Cells and Hypogammaglobulinemia

Marchbank

Kulik

Gipson

et al. 2002

The Journal of Immunology

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Complement receptor (CR) type 2 (CR2/CD21) is normally expressed only during the immature and mature stages of B cell development. In association with CD19, CR2 plays an important role in enhancing mature B cell responses to foreign Ag. We used a murine Vλ2 promoter/Vλ2–4 enhancer minigene to develop transgenic mice that initiate expression of human CR2 (hCR2) during the CD43+CD25− late pro-B cell stage of development. We found peripheral blood B cell numbers reduced by 60% in mice expressing high levels of hCR2 and by 15% in mice with intermediate receptor expression. Splenic B cell populations were altered with an expansion of marginal zone cells, and basal serum IgG levels as well as T-dependent immune responses were also significantly decreased in transgenic mice. Mice expressing the highest levels of hCR2 demonstrated in the bone marrow a slight increase in B220intCD43+CD25− B cells in association with a substantial decrease in immature and mature B cells, indicative of a developmental block in the pro-B cell stage. These data demonstrate that stage-specific expression of CR2 is necessary for normal B cell development, as premature receptor expression substantially alters this process. Alterations in B cell development are most likely due to engagement of pre-B cell receptor-mediated or other regulatory pathways by hCR2 in a CD19- and possibly C3 ligand-dependent manner.

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“…GGT expression on primary B cells and Ramos transfectants was determined by flow cytometry using the monoclonal antibody, 3A8 (15). GGT enzymatic activity in whole cell lysates was determined using a commercially available kinetic assay for the conversion of L-␥-glutamyl-3-carboxy-4-nitroanilide to 5-amino-2-nitrobenzoate in the presence of glycylglycine (Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Cells-Using a recently developed monoclonal antibody (3A8) to human GGT (15) and flow cytometry, expression of GGT by human T lymphocytes was previously found to increase with cellular activation (6). The same approach was used to assess the level of GGT expression on human B lymphocytes.…”

Section: Ggt-transfected Ramos Cells As a Model Of Activated Bmentioning

confidence: 99%

Expression of γ-Glutamyl Transpeptidase Protects Ramos B Cells from Oxidation-induced Cell Death

Karp

Shimooku

Lipsky

2001

Journal of Biological Chemistry

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175

119

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The ectoenzyme, ␥-glutamyl transpeptidase (GGT, EC 2.3.2.2) cleaves glutathione (GSH) to facilitate the recapture of cysteine for synthesis of intracellular GSH. The impact of GGT expression on cell survival during oxidative stress was investigated using the human B cell lymphoblastoid cell line, Ramos. Ramos cells did not express surface GGT and exhibited no GGT enzyme activity. In contrast, Ramos cells stably transfected with the human GGT cDNA expressed high levels of surface GGT and enzymatic activity. GGT-transfected Ramos cells were protected from apoptosis when cultured in cyst(e)ine-deficient medium. The GGT-expressing cells also had lower levels of intracellular reactive oxygen species (ROS). Homocysteic acid and alanine, inhibitors of cystine and cysteine uptake, respectively, caused increased ROS content and diminished viability of GGT expressing cells. Exogenous GSH increased the viability of the GGT-transfected cells more effectively than that of control cells, whereas the products of GSH metabolism prevented death of both the control and GGT-transfected cells comparably. These data indicate that GGT cleavage of GSH and the subsequent recapture of cysteine and cystine allow cells to maintain low levels of cellular ROS and thereby avoid apoptosis induced by oxidative stress. Glutathione (GSH)1 is the major intracellular nonprotein thiol defense against free radicals (1). It is a tripeptide consisting of glutamic acid, cysteine, and glycine. The antioxidant effect of GSH is dependent on the reduced sulfhydryl moiety of cysteine. Levels of intracellular GSH are maintained by a series of synthetic enzymes that regulate production of this tripeptide. Because of its relatively high intracellular concentration, GSH is transported out of cells into the extracellular environment. Once in the extracellular environment, there is little or no cellular uptake of intact glutathione. Rather, GSH is metabolized by ␥-glutamyl transpeptidase (GGT, EC 2.3.2.2), a plasma membrane enzyme whose catalytic site faces the extracellular environment (reviewed in Ref. 2). GGT removes the ␥-glutamyl group from GSH, after which cysteinylglycine can be cleaved by a membrane dipeptidase. The released cysteine can then be transported into the cell and used as a substrate for de novo synthesis of GSH. This ␥-glutamyl cycle is thought to maintain cellular GSH levels. Despite reports of GGT-related enzymes (3) or direct uptake of intact GSH by cells (4), the ␥-glutamyl cycle involving GGT is generally thought to be the major pathway by which cells utilize extracellular GSH for the de novo synthesis of intracellular GSH (5).We have recently shown that primary human memory T cells express higher level of GGT than naive T cells (6). Because these cells are specialized to access extravascular inflammatory sites (7), this observation suggests that increased GGT expression may provide an adaptive advantage in permitting these cells to resist oxidative stress and/or grow more effectively. This possibility is supported by the finding that T c...

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γ-glutamyl transpeptidase, an ecto-enzyme regulator of intracellular redox potential, is a component of TM4 signal transduction complexes

Cited by 56 publications

References 15 publications

Recruitment of CD63 toCryptococcus neoformansphagosomes requires acidification

Recruitment of CD63 toCryptococcus neoformansphagosomes requires acidification

Expression of Human Complement Receptor Type 2 (CD21) in Mice During Early B Cell Development Results in a Reduction in Mature B Cells and Hypogammaglobulinemia

Expression of γ-Glutamyl Transpeptidase Protects Ramos B Cells from Oxidation-induced Cell Death

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