Calcineurin Activation Is Only One Calcium-dependent Step in Cytotoxic T Lymphocyte Granule Exocytosis

Grybko, Michael J.; Bartnik, Jakub P.; Wurth, Georjeana A.; Pores-Fernando, Arun T.; Zweifach, Adam

doi:10.1074/jbc.m702222200

Cited by 18 publications

(37 citation statements)

References 47 publications

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“…In addition, pretreatment of CD8 + T cells with rapamycin for 3 days before coculture had no effect on the killing of infected cells ( Figure 3B). These findings are consistent with previous reports of the effect of these immunosuppressants on CTLs (20,21).…”

Section: Resultssupporting

confidence: 94%

“…Histone deacetylase inhibitors (HDACis), an otherwise promising class of LRAs, may interfere with CTL killing (19). Cyclosporin may also inhibit CTL function owing to a dependence of CTL degranulation on calcium influx and downstream signaling (20). In contrast, rapamycin has a positive effect on the memory CD8 + T cell response to viral infection (21).…”

Section: Integrated Proviruses In Resting Cd4mentioning

confidence: 99%

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Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity

Martin

Pollack

Capoferri

et al. 2017

Journal of Clinical Investigation

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Section: Resultssupporting

confidence: 94%

Section: Integrated Proviruses In Resting Cd4mentioning

confidence: 99%

Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity

Martin

Pollack

Capoferri

et al. 2017

Journal of Clinical Investigation

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“…In intracellular transport, calcineurin, in association with dynamin, has a central role in calcium-stimulated endocytosis in synaptosomes (41). Stimulatory (24,42,43) and inhibitory (44,45) roles for calcineurin in regulated exocytosis have also been reported. A role in acro- In resting sperm, SNAREs are assembled in inactive cis-complexes, and synaptotagmin is phosphorylated (a).…”

Section: Discussionmentioning

confidence: 99%

“…However, the target for the phosphatase activity of calcineurin in exocytosis has not been identified (47). The exocytosis of lytic granules by cytotoxic T lymphocytes (24) and natural killer cells (23) is inhibited by CsA and FK 506, but not by VIVIT, a peptide that specifically inhibits the interaction of calcineurin with NFAT, suggesting that the target for the phosphatase activity is a protein different from this transcription factor. Consistent with a role for calcineurin in human acrosomal exocytosis independent of NFAT, the secretion was sensitive to CsA, FK 506, and an anti-calcineurin antibody but resistant to VIVIT.…”

Section: Discussionmentioning

confidence: 99%

“…Calcineurin is a serine/threonine calcium/calmodulin-dependent protein phosphatase with essential roles in cell physiology (22). Calcineurin has been implicated in other exocytic processes (23,24), but a target for this protein in secretion has not been identified. It was then interesting to evaluate whether this phosphatase was responsible for the calcium-dependent dephosphorylation of synaptotagmin.…”

Section: Calcineurin Is Present In Human Sperm and It Is Required Atmentioning

confidence: 99%

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Calcineurin-mediated Dephosphorylation of Synaptotagmin VI Is Necessary for Acrosomal Exocytosis

Bennett¹,

Roggero²,

Mancifesta³

et al. 2010

Journal of Biological Chemistry

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Regulated secretion is a fundamental process underlying the function of many cell types. In particular, acrosomal exocytosis in mammalian sperm is essential for egg fertilization. In general, exocytosis is initiated by a cytosolic calcium increase. In this report we show that calcium affects several factors during human sperm acrosomal exocytosis. By using an antibody that specifically recognizes synaptotagmin VI phosphorylated at the polybasic region of the C2B domain, we showed that a calciumdependent dephosphorylation of this protein occurred at early stages of the acrosomal exocytosis in streptolysin O-permeabilized sperm. We identified the phosphatase as calcineurin and showed that the activity of this enzyme is absolutely required during the early steps of the secretory process. When added to sperm, an inhibitor-insensitive, catalytically active domain of calcineurin was able to rescue the effect of the specific calcineurin inhibitor cyclosporin A. This same domain dephosphorylated recombinant synaptotagmin VI C2B domain, validating this protein as a new substrate for calcineurin. When sperm were treated with catalytically active calcineurin before stimulation, exocytosis was inhibited, an effect that was rescued by the phosphomimetic synaptotagmin VI C2B-T418E,T419E mutant domain. These observations indicate that synaptotagmin must be dephosphorylated at a specific window of time and suggest that phosphorylated synaptotagmin has an active role at early stages of the acrosomal exocytosis.

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Extracellular Signal-Regulated Protein Kinase, c-Jun N-Terminal Protein Kinase, and Calcineurin Regulate Transient Receptor Potential M3 (TRPM3) Induced Activation of AP-1

2017

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Stimulation of transient receptor potential M3 (TRPM3) cation channels with pregnenolone sulfate induces an influx of Ca ions into the cells and a rise in the intracellular Ca concentration, leading to the activation of the activator protein-1 (AP-1) transcription factor. Here, we show that expression of a constitutively active mutant of the Ca /calmodulin-dependent protein phosphatase calcineurin attenuated pregnenolone sulfate-induced AP-1 activation in TRPM3-expressing cells. Likewise, expression of the regulatory B subunit of calcineurin reduced AP-1 activity in the cells following stimulation of TRPM3 channels. MAP kinase phosphatase-1 has been shown to attenuate TRPM3-mediated AP-1 activation. Here, we show that pregnenolone sulfate-induced stimulation of TRPM3 triggers the phosphorylation and activation of the MAP kinase extracellular signal-regulated protein kinase (ERK1/2). Pharmacological and genetic experiments revealed that stimulation of ERK1/2 is essential for the activation of AP-1 in cells expressing stimulated TRPM3 channels. ERK1/2 is required for the activation of the transcription factor c-Jun, a key component of the AP-1 transcription factor, and regulates c-Fos promoter activity. In addition, we identified c-Jun N-terminal protein kinase (JNK1/2) as a second signal transducer of activated TRPM3 channels. Together, the data show that calcineurin and the protein kinases ERK1/2 and JNK1/2 are important regulators within the signaling cascade connecting TRPM3 channel stimulation with increased AP-1-regulated transcription. J. Cell. Biochem. 118: 2409-2419, 2017. © 2017 Wiley Periodicals, Inc.

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Calcineurin Activation Is Only One Calcium-dependent Step in Cytotoxic T Lymphocyte Granule Exocytosis

Cited by 18 publications

References 47 publications

Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity

Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity

Calcineurin-mediated Dephosphorylation of Synaptotagmin VI Is Necessary for Acrosomal Exocytosis

Extracellular Signal-Regulated Protein Kinase, c-Jun N-Terminal Protein Kinase, and Calcineurin Regulate Transient Receptor Potential M3 (TRPM3) Induced Activation of AP-1

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