Calcineurin-dependent lytic granule exocytosis in NK-92 natural killer cells

Pores-Fernando, Arun T.; Gaur, Surabhi; Doyon, Michelle Y.; Zweifach, Adam

doi:10.1016/j.cellimm.2008.07.004

Cited by 18 publications

(19 citation statements)

References 24 publications

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“…Thus, it is possible that CsA blocked cytolysis by interfering with calcineurin function. On the other hand, this potential mechanism of action does not explain the long exposure times required for detecting CsArelated effects (Pores-Fernando et al, 2008). The IC 50 values determined for CsA in the NK cell killing and the whole-blood activation assay were near the value for peak blood levels in patients (Linnebacher et al, 2008), implicating that CsA could have an effect on NK cells in patients.…”

Section: Discussionmentioning

confidence: 93%

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Allosteric LFA-1 Inhibitors Modulate Natural Killer Cell Function

Weitz‐Schmidt

Chreng²,

Riek³

2008

Mol Pharmacol

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Natural killer (NK) cells are believed to play an important role in a variety of disease pathologies, including transplant rejection and autoimmunity. None of the therapeutic modalities currently available are known to potently interfere with NK cell activity. Here we demonstrate for the first time that low molecular weight inhibitors of the integrin lymphocyte function-associated antigen-1 (LFA-1) readily block NK cell adhesion, activation, and NK cell-mediated cytolysis in vitro, in contrast to other immunosuppressive agents. These effects were independent of the type of allosteric mechanism by which LFA-1 inhibition was achieved. In addition, we describe a simple, nonradioactive whole-blood assay that should be suitable to monitor NK cell activation in clinical practice. Taken together, our study underlines the importance of LFA-1 in NK cell effector functions and indicates that allosteric LFA-1 inhibitors may become important tools to further elucidate the therapeutic potential of NK cell modulation in immunological diseases.

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Section: Discussionmentioning

confidence: 93%

“…This delayed onset of activity clearly distinguished the effect of CsA from the immediate effects of the LFA-1 inhibitors. A recent study suggests that calcineurin is involved in NK-92 cell lytic granule exocytosis (Pores-Fernando et al, 2008). Thus, it is possible that CsA blocked cytolysis by interfering with calcineurin function.…”

Section: Discussionmentioning

confidence: 99%

Allosteric LFA-1 Inhibitors Modulate Natural Killer Cell Function

Weitz‐Schmidt

Chreng²,

Riek³

2008

Mol Pharmacol

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“…The absence of cognate KIR ligands on recipient cells can result in the recognition and subsequent attack by NK cells; hence, donor-derived NK cells have the potential to modulate GVHD and GVL [11]. Like T cells, NK cells express FKBP-12 (unpublished results) and calcineurin [12]. Therefore, they are likely to be a target for FK506 action.…”

Section: Introductionmentioning

confidence: 89%

FK506 causes cellular and functional defects in human natural killer cells

Kim

Kim²,

Kang

et al. 2010

Journal of Leukocyte Biology

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The role of NK cells in allogeneic HCT has been increasingly appreciated, particularly in the GVL effect. Although FK506 has been used widely to prevent GVHD, its action was considered to be primarily through activated T cells. In this study, we provide direct evidence for the first time that human NK cells are immediate targets of FK506. Our in vivo data from patients undergoing peripheral blood stem cell transplantation or BMT showed a reduced number of NK cells with down-regulated CD25 expression in their peripheral blood compartment. Likewise, FK506 caused profound inhibition of NK cell proliferation in vitro and suppressed NK cytotoxicity and cytokine secretion in response to IL-2. These defects were accompanied by impaired cell clustering and selective down-regulation of adhesion molecules, ICAM-1, CD2, CD49d, and CD58. Furthermore, FK506 specifically inhibited expression of NKG2D, CD48, and DNAM1 receptors without affecting that of 2B4, NKp30, NKp44, and NKp46. As a result, natural cytotoxicity against K562 tumor targets was impaired, while leaving redirected ADCC via 2B4 intact. Finally, FK506-treated NK cells showed impaired IL-2R signaling and inhibition of STAT3. Collectively, these signaling impairments and selective down-regulation of NK receptors by FK506 may underlie the proliferative and functional defects of NK cells. Thus, our data provide a new insight into the mechanism of immunosuppression by FK506, which should be considered to interpret the outcome of graft transplantation.

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“…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%

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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Calcineurin-dependent lytic granule exocytosis in NK-92 natural killer cells

Cited by 18 publications

References 24 publications

Allosteric LFA-1 Inhibitors Modulate Natural Killer Cell Function

Allosteric LFA-1 Inhibitors Modulate Natural Killer Cell Function

FK506 causes cellular and functional defects in human natural killer cells

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

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