Attenuated Natural Killer (NK) Cell Activation through C-type Lectin-like Receptor NKp80 Is Due to an Anomalous Hemi-immunoreceptor Tyrosine-based Activation Motif (HemITAM) with Impaired Syk Kinase Recruitment Capacity*
Attenuated Natural Killer (NK) Cell Activation through C-type Lectin-like Receptor NKp80 Is Due to an Anomalous Hemi-immunoreceptor Tyrosine-based Activation Motif (HemITAM) with Impaired Syk Kinase Recruitment Capacity*
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C 型凝集素样受体 NKp80 减弱自然杀伤 (NK) 细胞激活是由于异常的半免疫受体酪氨酸激活基序 (HemITAM) 与 Syk 激酶募集能力受损*
DOI：
10.1074/jbc.m113.453548
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
A. Steinle
中科院分区：
文献类型：
--
作者：
T. Rückrich;A. Steinle
细胞毒性是NK细胞介导病毒感染或恶性细胞的消除以及免疫应答调节的标志。NK细胞毒性在各种活化NK细胞受体的连接后被触发。其中包括C型凝集素样受体NKp 80，其在人类自然杀伤基因复合物（NKC）中编码，与其配体活化诱导的C型凝集素（AICL）相邻。NKp 80-AICL相互作用促进恶性髓系细胞的细胞溶解，但也刺激NK细胞和单核细胞之间的相互crosstalk.虽然许多活化的NK细胞受体与携带ITAM的衔接子配对，我们最近报道，NKp 80信号通过其胞质结构域中的半ITAM样序列。在这里，我们从分子水平上剖析了NKp 80 hemITAM，并证明了两个非共有氨基酸，特别是精氨酸6，严重损害了hemITAM磷酸化和Syk募集。受损的Syk募集导致NKp 80连接后细胞毒性应答的显著减弱。重建hemITAM共识或Syk过表达导致强大的NKp 80介导的反应性。总的来说，我们的数据提供了抑制NKp 80激活潜力的分子基础，并说明了信号基序的微妙变化如何决定随后的细胞反应。他们还表明，NKp 80 hemITAM中的非共有改变，如哺乳动物NKp 80序列中常见的那样，可能已经进化到抑制NKp 80介导的对AICL表达细胞的细胞毒性反应。背景：活化NK受体NKp 80通过细胞质hemITAM序列触发人NK细胞的细胞毒性。结果：非共有hemITAM残基损害NKp 80招募Syk激酶和触发细胞毒性的能力。结论：与典型的hemITAM受体不同，NKp 80不能有效地募集Syk激酶，从而导致效应子应答减弱。
Cellular cytotoxicity is the hallmark of NK cells mediating both elimination of virus-infected or malignant cells, and modulation of immune responses. NK cytotoxicity is triggered upon ligation of various activating NK cell receptors. Among these is the C-type lectin-like receptor NKp80 which is encoded in the human Natural Killer Gene Complex (NKC) adjacent to its ligand, activation-induced C-type lectin (AICL). NKp80-AICL interaction promotes cytolysis of malignant myeloid cells, but also stimulates the mutual crosstalk between NK cells and monocytes.While many activating NK cell receptors pair with ITAM-bearing adaptors, we recently reported that NKp80 signals via a hemITAM-like sequence in its cytoplasmic domain. Here we molecularly dissect the NKp80 hemITAM and demonstrate that two non-consensus amino acids, in particular arginine 6, critically impair both hemITAM phosphorylation and Syk recruitment. Impaired Syk recruitment results in a substantial attenuation of cytotoxic responses upon NKp80 ligation. Reconstituting the hemITAM consensus or Syk overexpression resulted in robust NKp80-mediated responsiveness. Collectively, our data provide a molecular rationale for the restrained activation potential of NKp80 and illustrate how subtle alterations in signaling motifs determine subsequent cellular responses. They also suggest that non-consensus alterations in the NKp80 hemITAM, as commonly present among mammalian NKp80 sequences, may have evolved to dampen NKp80-mediated cytotoxic responses toward AICL-expressing cells.Background:The activating NK receptor NKp80 triggers cytotoxicity by human NK cells via a cytoplasmic hemITAM sequence.Results:A non-consensus hemITAM residue impairs the capacity of NKp80 to recruit Syk kinase and to trigger cytotoxicity.Conclusion:Unlike typical hemITAM receptors, NKp80 does not efficiently recruit Syk kinase resulting in attenuated effector responses.Significance:An attenuated cytotoxic responsiveness critically impacts on the immunomodulatory function of NKp80.
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影响因子：
20.3
作者：
Kuttruff, Sabrina;Koch, Sven;Steinle, Alexander
通讯作者：
Steinle, Alexander
影响因子：
56.9
作者：
Bauer, S;Groh, V;Spies, T
通讯作者：
Spies, T
DOI：
10.1073/pnas.0913108107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Spreu, Jessica;Kuttruff, Sabrina;Steinle, Alexander
通讯作者：
Steinle, Alexander
影响因子：
20.3
作者：
Hughes CE;Pollitt AY;Mori J;Eble JA;Tomlinson MG;Hartwig JH;O'Callaghan CA;Fütterer K;Watson SP
通讯作者：
Watson SP
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影响因子：
4.4
作者：
R. Biassoni;M. Fogli;C. Cantoni;P. Costa;R. Conte;G. Koopman;A. Cafaro;B. Ensoli;A. Moretta;L. Moretta;A. De Maria
通讯作者：
A. De Maria