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在T细胞中的表面PD-1表达被HNRNPK通过3号外子上的外子拼接声器抑制

Jiayun Wang¹, Lingyan Yan¹, Xu Wang¹

¹State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.

Inflammation research : official journal of the European Histamine Research Society ... [et al.]

|May 2, 2024

概括

研究人员确定异质核核核糖核蛋白K (HNRNPK) 是调节编程细胞死亡1 (PD-1) 表达的关键因素. HNRNPK促进PD-1外因子3跳转,减少表面PD-1和增加可溶性PD-1,影响免疫反应.

科学领域:

免疫学免疫学免疫学
分子生物学分子生物学
遗传学遗传学是一种遗传学.

背景情况:

针对PD-1的免疫疗法显示出希望,需要了解PD-1表达调节.
跳过PD-1外显子3产生溶性PD-1 (sPD-1),通过与表面PD-1 (flPD-1) 竞争来增强免疫反应.
PD-1外因子3跳转的确切机制尚不清楚.

研究的目的:

为了阐明PD-1外因子3跳转的调节机制.
为了确定参与PD-1替代拼接的拼接因素.
为了研究PD-1外因子3跳过PD-1表达的功能后果.

主要方法:

使用SpliceAid程序和小基因系统来识别拼接因素.
采用现场定向的突变发生和拉下测试来验证HNRNPK结合.
合成和选的反感性寡核化物 (ASOs) 抑制了外显子3跳转.
通过RT-PCR分析了替代拼接,并通过西方斑点和流动细胞计量进行了蛋白质表达.

主要成果:

异质核核核糖核蛋白K (HNRNPK) 被确定为促进PD-1外形3跳转的关键拼接因子.
HNRNPK与PD-1外体3上的外体拼接声器 (ESS) 结合,从而促进跳转.
通过ASO介导的HNRNPK-ESS相互作用的抑制显著降低了异构3跳转.
由HNRNPK诱导的3外因子跳转降低了flPD-1和增加了sPD-1的表达.
这种调节机制在小鼠中保留了.

结论:

发现了一种新的,进化保守的调节PD-1表达的机制.
通过与ESS结合,HNRNPK促进PD-1外因子3跳转.
这种拼接事件导致T细胞中的flPD-1减少和sPD-1增加,影响免疫功能.

关键词:

异声拼接沉声器异声拼接沉声器不同质的核核核糖核蛋白K.编程细胞死亡 1 编程细胞死亡

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