A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands.
A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands.
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DOI：
10.1126/scisignal.abc4479
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发表时间：
2021-02-02
影响因子：
7.3
通讯作者：
Weiss A
中科院分区：
文献类型：
--
作者：
Shen L;Matloubian M;Kadlecek TA;Weiss A
胞浆蛋白激酶ZAP70在T细胞抗原受体(TCR)信号转导中起关键作用。ZAP70基因R360P突变与早发性家族性自身免疫综合征有关。R360P突变的结构定位和生化信号作用与ZAP70自身抑制构象的减弱一致。携带ZAP70R360P突变和多克隆TCR谱系的小鼠表现出相对正常的T细胞发育，但显示出信号增强的证据。此外，在LCMV感染后，R360P突变导致滤泡辅助性T细胞增殖增强。为了消除TCR谱系改变的可能性，将OTI转基因TCR引入R360P小鼠，导致T细胞对弱刺激的反应增强，包括弱激动剂和自体肽。这些观察表明，R360P突变破坏ZAP70自身抑制使成熟T细胞对通常被野生型T细胞忽略的自身抗原的敏感性增加，这一机制可能有助于打破R360P突变患者的耐受性。
The cytoplasmic kinase ZAP70 is critical for T cell antigen receptor (TCR) signaling. The R360P mutation in ZAP70 is responsible for an early onset familial autoimmune syndrome. The structural location and biochemical signaling effects of the R360P mutation are consistent with weakening of the autoinhibitory conformation of ZAP70. Mice with a ZAP70 R360P mutation and polyclonal TCR repertoires exhibited relatively normal T cell development but showed evidence of increased signaling. Additionally, the R360P mutation resulted in enhanced follicular helper T cell expansion after LCMV infection. To eliminate the possibility of a TCR repertoire shift, the OTI transgenic TCR was introduced into R360P mice, which resulted in enhanced T cell responses to weaker stimuli, including weak agonists and a self-peptide. These observations suggest that disruption of ZAP70 autoinhibition by the R360P mutation enables increased mature T cell sensitivity to self-antigens that would normally be ignored by wild-type T cells, a mechanism that may contribute to the break of tolerance in human patients with R360P mutation.
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ZAP-70 的亚等位基因揭示了自身免疫性疾病与自身免疫反应性的不同胸腺阈值。
DOI：
10.1084/jem.20082902
发表时间：
2009-10-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hsu LY;Tan YX;Xiao Z;Malissen M;Weiss A
通讯作者：
Weiss A
影响因子：
64.5
作者：
Deindl, Sebastian;Kadlecek, Theresa A.;Kuriyan, John
通讯作者：
Kuriyan, John
影响因子：
64.8
作者：
NEGISHI, I;MOTOYAMA, N;LOH, DY
通讯作者：
LOH, DY
影响因子：
64.8
作者：
Sakaguchi, N;Takahashi, T;Sakaguchi, S
通讯作者：
Sakaguchi, S
DOI：
10.1073/pnas.0807309106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Bubier, Jason A.;Sproule, Thomas J.;Roopenian, Derry C.
通讯作者：
Roopenian, Derry C.