文章基本信息

标题：ADP-ribose/TRPM2-mediated Ca²⁺ signaling is essential for cytolytic degranulation and antitumor activity of natural killer cells
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作者：So-Young Rah ; Jae-Yong Kwak ; Yun-Jo Chung 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2015
卷号：5
DOI：10.1038/srep09482
出版社：Springer Nature
摘要：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.