Human microRNA-27a*targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity
Human microRNA-27a*targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity
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DOI：
10.1182/blood-2011-04-347526
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发表时间：
2011-11-17
期刊：
影响因子：
20.3
通讯作者：
Choi, Inpyo
中科院分区：
文献类型：
--
作者：
Kim, Tae-Don;Lee, Su Ui;Choi, Inpyo
穿孔蛋白（Prf 1）和颗粒酶B（Gzm B）是自然杀伤（NK）细胞毒性的必需效应分子，但在NK细胞的武装期间如何调节Prf 1和Gzm B表达尚不清楚。我们发现，人类microRNA（miR）-27 a * 是通过沉默Prf 1和GzmB表达的NK细胞毒性的负调节因子。人miR-27 a * 特异性结合Prf 1和GzmB的3'非翻译区，下调静息和活化NK细胞中的表达，并且其作为效应蛋白净量的稳态的微调器发挥作用。与具有抑制作用的miR-27 a * 一致，NK细胞中miR-27 a * 的敲低显著增加体外细胞毒性并减少人肿瘤异种移植模型中的肿瘤生长。因此，NK细胞的细胞毒性部分地由microRNA调节，并且调节NK细胞中的内源性miR-27 a * 水平代表了潜在的免疫抑制策略。（血。2011;118（20）：5476-5486）
Perforin (Prf1) and granzyme B (GzmB) are essential effector molecules for natural killer (NK)-cell cytotoxicity, but how Prf1 and GzmB expression is regulated during arming of NK cells is poorly defined. We show that human microRNA (miR)-27a* is a negative regulator of NK-cell cytotoxicity by silencing Prf1 and GzmB expression. Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells, and it functioned as a fine-tuner for homeostasis of the net amount of the effector proteins. Consistent with miR-27a* having an inhibitory role, knockdown of miR-27a* in NK cells dramatically increased cytotoxicity in vitro and de-creased tumor growth in a human tumor xenograft model. Thus, NK-cell cytotoxicity is regulated, in part, by microRNA, and modulating endogenous miR-27a* levels in NK cells represents a potential immunotherapeutic strategy. (Blood. 2011;118(20):5476-5486)