NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins
NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins
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DOI：
10.1126/science.1151227
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发表时间：
2008-01-25
期刊：
影响因子：
56.9
通讯作者：
Worley, Paul F.
中科院分区：
文献类型：
--
作者：
Huang, Guo N.;Huso, David L.;Worley, Paul F.
T细胞受体(TCR)和共刺激受体(CD28)信号在激活T细胞方面协同作用，尽管对这些途径本身是如何调节的了解还不完全。我们发现Hmer家族的胞质支架蛋白Hmer 2和Hmer 3是T细胞激活的负调节因子。这是通过结合活化的T细胞核因子(NFAT)和与钙调神经磷酸酶竞争来实现的。激活的丝氨酸苏氨酸激酶AKT也能拮抗Homer-NFAT的结合，从而通过依赖钙调神经磷酸酶的NFAT去磷酸化来增强TCR信号。这与荷马缺陷小鼠细胞因子表达的变化和效应记忆T细胞群的增加相对应，这也发展了自身免疫性病理。这些结果证明了调节共刺激信号以控制自身反应性的另一种方法。
T cell receptor ( TCR) and costimulatory receptor ( CD28) signals cooperate in activating T cells, although understanding of how these pathways are themselves regulated is incomplete. We found that Homer2 and Homer3, members of the Homer family of cytoplasmic scaffolding proteins, are negative regulators of T cell activation. This is achieved through binding of nuclear factor of activated T cells ( NFAT) and by competing with calcineurin. Homer-NFAT binding was also antagonized by active serine- threonine kinase AKT, thereby enhancing TCR signaling via calcineurin- dependent dephosphorylation of NFAT. This corresponded with changes in cytokine expression and an increase in effector- memory T cell populations in Homer- deficient mice, which also developed autoimmune- like pathology. These results demonstrate a further means by which costimulatory signals are regulated to control self- reactivity.