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 Blood, 15 April 2008, Vol. 111, No. 8, pp. 4165-4172.
Prepublished online as a Blood First Edition Paper on December 11, 2007; DOI 10.1182/blood-2007-08-108886.

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IMMUNOBIOLOGY

PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway

Federica Micucci*,1, Cristina Capuano*,1, Enzo Marchetti2, Mario Piccoli1, Luigi Frati1,3, Angela Santoni1, and Ricciarda Galandrini1

1 Department of Experimental Medicine, Istituto Pasteur-Fondazione Cenci-Bolognetti, Rome; 2 Department of Genetic and Molecular Biology, Sapienza University, Rome; and 3 Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, Italy

Although membrane phospholipid phosphatidylinositol-4,5bisphosphate (PIP2) plays a key role as signaling intermediate and coordinator of actin dynamics and vesicle trafficking, it remains completely unknown its involvement in the activation of cytolytic machinery. By live confocal imaging of primary human natural killer (NK) cells expressing the chimeric protein GFP-PH, we observed, during effector-target cell interaction, the consumption of a preexisting PIP2 pool, which is critically required for the activation of cytolytic machinery. We identified type I phosphatidylinositol-4-phosphate-5-kinase (PI5KI) {alpha} and {gamma} isoforms as the enzymes responsible for PIP2 synthesis in NK cells. By hRNA-driven gene silencing, we observed that both enzymes are required for the proper activation of NK cytotoxicity and for inositol-1,4,5-trisphosphate (IP3) generation on receptor stimulation. In an attempt to elucidate the specific step controlled by PI5KIs, we found that lytic granule secretion but not polarization resulted in impaired PI5KI{alpha}- and PI5KI{gamma}-silenced cells. Our findings delineate a novel mechanism implicating PI5KI{alpha} and PI5KI{gamma} isoforms in the synthesis of PIP2 pools critically required for IP3-dependent Ca2+ response and lytic granule release.


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Related Article in Blood Online:

Below the NK-cell surface: PIP2
Marco Colonna
Blood 2008 111: 3916. [Full Text] [PDF]





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