ADP-ribose/TRPM2-mediated Ca2+ signaling is essential for cytolytic degranulation and antitumor activity of natural killer cells
Open Access
- 25 March 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 5 (1), srep09482-9482
- https://doi.org/10.1038/srep09482
Abstract
Natural killer (NK) cells are essential for immunosurveillance against transformed cells. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel gated by ADP-ribose (ADPR). However, the role of TRPM2-mediated Ca2+ signaling in the antitumor response of NK cells has not been explored. Here, we show that ADPR-mediated Ca2+ signaling is important for cytolytic granule polarization and degranulation but not involved in target cell recognition by NK cells. The key steps of this pathway are: 1) the activation of intracellular CD38 by protein kinase A following the interaction of the NK cell with a tumor cell results in the production of ADPR, 2) ADPR targets TRPM2 channels on cytolytic granules, and 3) TRPM2-mediated Ca2+ signaling induces cytolytic granule polarization and degranulation, resulting in antitumor activity. NK cells treated with 8-Br-ADPR, an ADPR antagonist, as well as NK cells from Cd38−/− mice showed reduced tumor-induced granule polarization, degranulation, granzyme B secretion, and cytotoxicity of NK cells. Furthermore, TRPM2-deficient NK cells showed an intrinsic defect in tumoricidal activity. These results highlight CD38, ADPR, and TRPM2 as key players in the specialized Ca2+ signaling system involved in the antitumor activity of NK cells.This publication has 42 references indexed in Scilit:
- NAADP Activates Two-Pore Channels on T Cell Cytolytic Granules to Stimulate Exocytosis and KillingCurrent Biology, 2012
- Transient Receptor Potential Melastatin 2 (TRPM2) ion channel is required for innate immunity againstListeria monocytogenesProceedings of the National Academy of Sciences of the United States of America, 2011
- ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysisProceedings of the National Academy of Sciences of the United States of America, 2011
- The Ecto-enzyme CD38 Is a Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Synthase That Couples Receptor Activation to Ca2+ Mobilization from Lysosomes in Pancreatic Acinar CellsPublished by Elsevier BV ,2010
- Generation of Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate by CD38 for Ca2+ Signaling in Interleukin-8-treated Lymphokine-activated Killer CellsJournal of Biological Chemistry, 2010
- Intracellular calcium activates TRPM2 and its alternative spliced isoformsProceedings of the National Academy of Sciences of the United States of America, 2009
- Hydrolase Regulates NAD+ Metabolites and Modulates Cellular RedoxPublished by Elsevier BV ,2009
- Formation and function of the lytic NK-cell immunological synapseNature Reviews Immunology, 2008
- Regulation of TRPM2 by Extra- and Intracellular CalciumThe Journal of general physiology, 2007
- Functional significance of the perforin/granzyme cell death pathwayNature Reviews Immunology, 2002