Sahoo Anupama, Alekseev Andrei, Obertas Lidiya, Nurieva Roza
Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Nat Commun. 2014 Aug 22;5:4732. doi: 10.1038/ncomms5732.
T helper (Th)-2 cells are the major players in allergic asthma; however, the mechanisms that control Th2-mediated inflammation are poorly understood. Here we find that enhanced expression of Grail, an E3 ubiquitin ligase, in Th2 cells depends on interleukin (IL)-4-signalling components, signal transducer and activator of transcription 6 (Stat6) and Gata3, that bind to and transactivate the Grail promoter. Grail deficiency in T cells leads to increased expression of Th2 effector cytokines in vitro and in vivo and Grail-deficient mice are more susceptible to allergic asthma. Mechanistically, the enhanced effector function of Grail-deficient Th2 cells is mediated by increased expression of Stat6 and IL-4 receptor α-chain. Grail interacts with Stat6 and targets it for ubiquitination and degradation. Thus, our results indicate that Grail plays a critical role in controlling Th2 development through a negative feedback loop.
辅助性T细胞2（Th2）是过敏性哮喘的主要参与者；然而，控制Th2介导的炎症的机制仍知之甚少。我们发现，E3泛素连接酶Grail在Th2细胞中的表达增强依赖于白细胞介素（IL）-4信号传导成分、信号转导和转录激活因子6（Stat6）以及与Grail启动子结合并使其反式激活的Gata3。T细胞中Grail缺陷导致体外和体内Th2效应细胞因子表达增加，且Grail缺陷小鼠对过敏性哮喘更易感。从机制上讲，Grail缺陷的Th2细胞增强的效应功能是由Stat6和IL-4受体α链表达增加介导的。Grail与Stat6相互作用并将其靶向泛素化和降解。因此，我们的结果表明，Grail通过负反馈回路在控制Th2发育中起关键作用。
