Association of supervillin with KIR2DL1 regulates the inhibitory signaling of natural killer cells.
Inhibitory signaling is crucial in the regulation of the cytotoxicity of natural killer (NK) cells. Here, we show that KIR2DL1, an inhibitory receptor of NK cells, associates with supervillin, an F-actin binding protein. Interaction of supervillin with KIR2DL1 is dependent on the KIR2DL1 receptor stimulation and requires the phosphorylation of tyrosines in both ITIM motifs. "Knockdown" of expression of supervillin by RNA interference (RNAi) restores the KIR2DL1-suppressed cytotoxicity of NK cells. Inhibition of supervillin by RNAi also enhances the polarization of cytolytic granules (both granzyme B and perforin) to the synapse formed between YTS-GFP-KIR2DL1 NK cells and 721.221-HLA-Cw4 target cells. Further study reveals that supervillin is required for KIR2DL1-mediated inhibition of Vav1 and ERK phoshorylation. Moreover, we have found that binding of supervillin with KIR2DL1 facilitates the recruitment of SHPs especially SHP-2 to KIR2DL1 receptor. Thus, our findings demonstrate that supervillin is a novel molecule that associates with KIR2DL1 receptor and regulates the inhibitory signaling in NK cells.
Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (CAS), China.
Hai-Peng
HP
Liu
Ming-Can
MC
Yu
Meng-Hui
MH
Jiang
Jian-Xia
JX
Chen
Da-Peng
DP
Yan
Feng
F
Liu
Bao-Xue
BX
Ge
D020816:Amino Acid Motifs; D002461:Cell Line, Transformed; D016384:Consensus Sequence; D003602:Cytotoxicity, Immunologic; D057809:HEK293 Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D034622:RNA Interference; D054342:Receptors, KIR2DL1 / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
C093100:KIR2DL1 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D054342:Receptors, KIR2DL1; C109413:SVIL protein, human; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6