title: ADP-ribose/TRPM2-mediated Ca2+ signaling is essential for cytolytic degranulation and antitumor activity of natural killer cells.
abstract: Natural killer (NK) cells are essential for immunosurveillance against transformed cells. Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+)-permeable cation channel gated by ADP-ribose (ADPR). However, the role of TRPM2-mediated Ca(2+) signaling in the antitumor response of NK cells has not been explored. Here, we show that ADPR-mediated Ca(2+) 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 Ca(2+) 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 Ca(2+) signaling system involved in the antitumor activity of NK cells.
authors: 1] Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Republic of Korea [2] National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors: So-Young
authors: SY
authors: Rah
authors: 1] National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Republic of Korea [2] Division of Hematology and Oncology, Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea [3] Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors: Jae-Yong
authors: JY
authors: Kwak
authors: National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors: Yun-Jo
authors: YJ
authors: Chung
authors: 1] Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Republic of Korea [2] National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Republic of Korea [3] Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors: Uh-Hyun
authors: UH
authors: Kim
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D015550:Cell Degranulation; D016764:Cell Polarity; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005089:Exocytosis; D053804:Granzymes / Q000378:metabolism; D007477:Ions / Q000737:chemistry; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050053:TRPM Cation Channels / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D007477:Ions; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D000246:Adenosine Diphosphate Ribose; D017868:Cyclic AMP-Dependent Protein Kinases; D051997:ADP-ribosyl Cyclase 1; D053804:Granzymes; D002118:Calcium