期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 25, 页码 17647-17657出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.572420
关键词
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资金
- National Natural Science Foundation of China [81330047, 31170837, 30830030, 30972676]
- 973 Program of the MOST of China [2010CB911902]
- Strategic Priority Research Programs of the Chinese Academy of Sciences [XDA01010407]
Natural killer (NK) cell activation is well orchestrated by a wide array of NK cell receptor repertoire. T-cell immunoglobulin and ITIM domain (TIGIT) receptor was recently defined as an inhibitory receptor that is expressed on NK cells and T cells. TIGIT receptor/poliovirus receptor (PVR) ligand engagement signaling inhibits cytotoxicity mediated by NK and CD8(+) T cells. However, it is unclear how TIGIT/PVR signaling regulates cytokine secretion in NK cells. Here we show that TIGIT/PVR engagement suppresses interferon-gamma (IFN-gamma) production of NK cells. TIGIT transgenic NK cells generate less IFN-gamma undergoing TIGIT/PVR ligation. Moreover, TIGIT knock-out NK cells produce much more IFN-gamma. TIGIT/PVR ligation signaling mediates suppression of IFN-gamma production via the NF-kappa B pathway. We identified a novel adaptor beta-arrestin 2 that associates with phosphorylated TIGIT for further recruitment of SHIP1 (SH2-containing inositol phosphatase 1) through the ITT-like motif. Importantly, SHIP1, but not other phosphatases, impairs the TNF receptor-associated factor 6 (TRAF6) autoubiquitination to abolish NF-kappa B activation, leading to suppression of IFN-gamma production in NK cells.
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