PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.
PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis.
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DOI：
10.1371/journal.pone.0033067
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ho IC
中科院分区：
文献类型：
--
作者：
Chang HH;Tai TS;Lu B;Iannaccone C;Cernadas M;Weinblatt M;Shadick N;Miaw SC;Ho IC
PTPN 22是酪氨酸磷酸酶，并且作为TCR信号的阻尼器起作用。位于人PTPN 22 cDNA第1858位并将精氨酸（R620）转化为色氨酸（W 620）的C-to-T单核苷酸多态性（SNP）在已知与该疾病相关的非HLA遗传变异中赋予类风湿性关节炎最高的风险。R-to-W转换对PTPN 22蛋白磷酸酶活性的影响以及C1858 T SNP的次要T等位基因对T细胞活化的影响仍然存在争议。此外，PTPN 22的整体活性如何调节以及R-W转换如何导致类风湿性关节炎仍然知之甚少。在这里，我们报告了人类PTPN 22的选择性剪接形式的鉴定，即PTPN 22.6。它缺乏几乎完整的磷酸酶结构域，可以作为全长PTPN 22的显性负性同种型发挥作用。尽管在PTPN 22.1的情况下R620向W 620的转化减弱了T细胞活化，但PTPN 22.6的色氨酸变体的表达导致人T细胞的超活化。更重要的是，外周血中PTPN 22.6的水平与类风湿性关节炎的疾病活动性相关。我们的数据描述了一个模型，可以调和C1858 T SNP功能影响的相互矛盾的观察结果，也表明PTPN22.6是类风湿关节炎的一种新的生物标志物。
PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals. A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease. The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial. In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood. Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6. It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22. Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells. More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis. Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.
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影响因子：
5.3
作者：
Kang, BY;Miaw, SC;Ho, IC
通讯作者：
Ho, IC
影响因子：
30.8
作者：
Vang, T;Congia, M;Bottini, N
通讯作者：
Bottini, N
影响因子：
2.9
作者：
Liu, Yingge;Stanford, Stephanie M.;Jog, Sonali P.;Fiorillo, Edoardo;Orru, Valeria;Comai, Lucio;Bottini, Nunzio
通讯作者：
Bottini, Nunzio
DOI：
10.4049/jimmunol.0803317
发表时间：
2009-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Zikherman J;Hermiston M;Steiner D;Hasegawa K;Chan A;Weiss A
通讯作者：
Weiss A
影响因子：
30.8
作者：
Bottini, N;Musumeci, L;Mustelin, T
通讯作者：
Mustelin, T