Inhibition of cytolysin activity in large granular lymphocyte granules by lipids: Evidence for a membrane insertion mechanism of lysis

Yue, Cheung Cho; Reynolds, Craig W.; Henkart, Pierre A.

doi:10.1016/0161-5890(87)90046-0

Cited by 31 publications

(4 citation statements)

References 28 publications

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“…Elucidation of a possible role of PC-PLC in the molecular events occurring at the synapse region may shed new light on PFN-mediated lytic mechanisms. Yue et al [7] provided indirect evidence in support of a possible involvement of PC-PLC in cell killing, demonstrating that free PCho was specifically able to inhibit the lytic activity of isolated granules. As shown by our confocal observations, PC-PLC is recruited to the immune synapse pocket, where it could be in an appropriate position to hydrolyze the PC molecules exposed on the outer membrane bilayer of target cells.…”

Section: Discussionmentioning

confidence: 99%

“…PFN are phospholipid-binding proteins that can damage the membrane of mammalian cells by insertion in the lipid bilayer, resulting in pore formation. The molecular mechanisms underlying these cytotoxic effects are not known in detail, although previous studies have pointed to a possible involvement of phosphocholine (PCho), the phosphatidylcholine (PC) headgroup, as a Ca +2 -dependent receptor for PFN and to a role of free PCho, product of phospholipase-mediated PC hydrolysis, as a possible inhibitor of isolated granules' cytotoxicity [6,7]. Hydrolysis of PC, the major phospholipid in eukaryotic cell membranes, involves distinct classes of phospholipases, including phospholipases A 2 (PLA 2 ), C (PC-PLC) and D (PLD).…”

Section: Introductionmentioning

confidence: 99%

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Expression and role of phosphatidylcholine‐specific phospholipase C in human NK and T lymphocyte subsets

et al. 2006

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We recently reported evidence of phosphatidylcholine-specific phospholipase C (PC-PLC) involvement in NK cell-mediated cytotoxicity and in lytic granule exocytosis. In the present study, different subpopulations of human PBL were investigated in relation to PC-PLC enzyme expression. While a substantial intracellular amount of PC-PLC was detected in all lymphoid subsets, expression of this enzyme on the outer membrane surface reached high levels only in NK cells, was present at low levels in B lymphocytes and in some TCR gamma/delta T cells and was practically absent in CD4 + and CD8 + T lymphocytes. Moreover, in NK cells two different subpopulations were identified, CD56 dim PC-PLC bright and CD56 bright PC-PLC low/-cells, corresponding to distinct subsets with cytolytic and immunoregulatory functions, respectively. Interestingly, the PC-PLC expression level on the NK membrane surface correlated closely with that of the CD16 receptor, suggesting a possible relationship between enzyme externalization and NK cell maturation. In summary, our results suggest that a high PC-PLC expression on the cell membrane surface of PBL is a peculiarity of NK cytolytic cells, in which the enzyme is apparently involved in the ability of this subset to lyse sensitive target cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression and role of phosphatidylcholine‐specific phospholipase C in human NK and T lymphocyte subsets

et al. 2006

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“…Indirect evidence in support of a possible role of PC-PLC in NK-mediated cell killing was provided by the dose-dependent inhibition exerted on the lytic activity of isolated cytotoxic granules by free phosphocholine (PCho), a product of PLC-mediated PC hydrolysis (23). This compound, which represents the predominant headgroup esterified to phospholipids on the outer leaflet of the plasma membrane of eukaryotic cells, was the most potent inhibitor of granule cytolytic activity among various phosphomonoesters (e.g., glycerophosphate, phosphoethanolamine) or nonphosphorylated derivatives of phospholipid headgroups (choline, ethanolamine).…”

mentioning

confidence: 99%

Cellular Localization and Functional Role of Phosphatidylcholine-Specific Phospholipase C in NK Cells

Ramoni¹,

Spadaro²,

Menegon³

et al. 2001

The Journal of Immunology

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Although several classes of phospholipases have been implicated in NK cell-mediated cytotoxicity, no evidence has been reported to date on involvement of phosphatidylcholine-specific phospholipase C (PC-PLC) in NK activation by lymphokines and/or in lytic granule exocytosis. This study demonstrated the expression of two PC-PLC isoforms (M(r) 40 and 66 kDa) and their IL-2-dependent distribution between cytoplasm and ectoplasmic membrane surface in human NK cells. Following cell activation by IL-2, cytoplasmic PC-PLC translocated from the microtubule-organizing center toward cell periphery, essentially by kinesin-supported transport along microtubules, while PC-PLC exposed on the outer cell surface increased 2-fold. Preincubation of NK cells with a PC-PLC inhibitor, tricyclodecan-9-yl-xanthogenate, strongly reduced NK-mediated cytotoxicity. In IL-2-activated cells, this loss of cytotoxicity was associated with a decrease of PC-PLC exposed on the cell surface, and accumulation of cytoplasmic PC-PLC in the Golgi region. Massive colocalization of PC-PLC-rich particles with perforin-containing granules was found in the cytoplasm of NK-activated (but not NK-resting) cells; both organelles clustered at the intercellular contact region of effector-target cell conjugates. These newly detected mechanisms of PC-PLC translocation and function support an essential role of this enzyme in regulated granule exocytosis and NK-mediated cytotoxicity.

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“…The granule component responsible for this permeabilization is perforin, a complement-related pore-forming protein. With Ca2+, perforin can insert into target cell membranes, where it polymerizes to form nonspecific ion channels (8)(9)(10). Formation of these ion channels appears sufficient to induce the lysis of certain cell types.…”

mentioning

confidence: 99%

Identification and functional characterization of a TIA-1-related nucleolysin.

Kawakami

Tian

Duan

et al. 1992

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

156

127

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We recently reported the molecular cloning of a cytotoxic granule-associated RNA-binding protein designated TIA-1. The ability of recombinant TIA-1 to induce DNA fragmentation in permeabilized cells suggested that this protein is the granule component responsible for inducing apoptosis in cytolytic lymphocyte (CTL) targets. Here we report the characterization of a cDNA encoding a TIA-1-related protein designated TIAR. The deduced amino acid sequence of TIAR reveals it to be a 42-kDa protein possessing three RNA-binding domains and a carboxyl-terminal auxiliary domain. Although the RNA-binding domains of TIA-1 and TIAR share >85% amino acid homology, their carboxyl-terminal auxiliary domains are only 51% homologous. The carboxyl terminus of TIAR contains a lysosome-targeting motif, indicating that TUAR is probably a cytotoxic granule-associated protein. Like TIA-1, purified recombinant TIAR induced DNA fragmentation in permeabilized target cells. Although immunoblotting analysis of post-nuclear supernatants revealed TIA-1 protein to be restricted to CTLs, PCR analysis revealed the expression of TIA-1 and TIAR mRNA transcripts in a wide variety of cell types. Our data suggest that the granules of CTLs contain at least two candidate nucleolysins involved in CTL killing.

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Inhibition of cytolysin activity in large granular lymphocyte granules by lipids: Evidence for a membrane insertion mechanism of lysis

Cited by 31 publications

References 28 publications

Expression and role of phosphatidylcholine‐specific phospholipase C in human NK and T lymphocyte subsets

Expression and role of phosphatidylcholine‐specific phospholipase C in human NK and T lymphocyte subsets

Cellular Localization and Functional Role of Phosphatidylcholine-Specific Phospholipase C in NK Cells

Identification and functional characterization of a TIA-1-related nucleolysin.

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