SOCS-6 通过将 p56lck 靶向到蛋白酶体降解来负调控 T 细胞激活。
SOCS-6 negatively regulates T cell activation through targeting p56lck to proteasomal degradation.
机构信息
Department of Life Science, Ewha Woman's University, 120-750 Seoul, Korea.
出版信息
J Biol Chem. 2010 Mar 5;285(10):7271-80. doi: 10.1074/jbc.M109.073726. Epub 2009 Dec 10.
Abstract
The T cell-specific tyrosine kinase, p56(lck), plays crucial roles in T cell receptor (TCR)-mediated T cell activation. Here, we report that SOCS-6 (suppressor of cytokine signaling-6) is a negative regulator of p56(lck). SOCS-6 was identified as a protein binding to the kinase domain of p56(lck) through yeast two-hybrid screening. SOCS-6 bound specifically to p56(lck) (F505), which mimics the active form of p56(lck), but not to wild type p56(lck). In Jurkat T cells, SOCS-6 binding to p56(lck) was detected 1-2 h after TCR stimulation. Confocal microscopy showed that upon APC-T cell conjugation, SOCS-6 was recruited to the immunological synapse and colocalized with the active form of p56(lck). SOCS-6 promoted p56(lck) ubiquitination and its subsequent targeting to the proteasome. Moreover, SOCS-6 overexpression led to repression of TCR-dependent interleukin-2 promoter activity. These results establish that SOCS-6 acts as a negative regulator of T cell activation by promoting ubiquitin-dependent proteolysis.
摘要
T 细胞特异性酪氨酸激酶 p56(lck) 在 T 细胞受体 (TCR) 介导的 T 细胞激活中发挥关键作用。在这里，我们报告 SOCS-6（细胞因子信号转导抑制剂-6）是 p56(lck) 的负调控因子。通过酵母双杂交筛选，SOCS-6 被鉴定为与 p56(lck) 的激酶结构域结合的蛋白。SOCS-6 特异性结合 p56(lck)(F505)，模拟 p56(lck) 的活性形式，但不与野生型 p56(lck)结合。在 Jurkat T 细胞中，TCR 刺激后 1-2 小时即可检测到 SOCS-6 与 p56(lck) 的结合。共聚焦显微镜显示，在 APC-T 细胞连接后，SOCS-6 被募集到免疫突触，并与 p56(lck)的活性形式共定位。SOCS-6 促进 p56(lck)的泛素化及其随后被靶向到蛋白酶体。此外，SOCS-6 的过表达导致 TCR 依赖性白细胞介素-2 启动子活性受到抑制。这些结果表明，SOCS-6 通过促进泛素依赖性蛋白水解作用，作为 T 细胞激活的负调控因子发挥作用。
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