A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation
A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation
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DOI：
10.1016/j.immuni.2007.11.020
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发表时间：
2008-01-01
期刊：
影响因子：
32.4
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
--
作者：
Matza, Didi;Badou, Abdallah;Flavell, Richard A.
在抗原呈递过程中，T细胞抗原受体(TCR)的参与启动了大量信号蛋白和离子通道的协调作用。AHNAK1是一种支架蛋白，由CD4(+)T细胞高度表达，是钙信号转导的关键成分。我们发现AHNAK1基因缺陷的小鼠对利什曼原虫感染高度敏感。AHNAK1缺陷的CD4(+)T细胞在体外对TCR刺激反应差，低增殖和低IL-2产生。此外，AHNAK1缺乏导致TCR交联时钙内流减少，从而导致转录因子NFAT的激活不良。AHNAK1是L型钙通道α1S(Ca(V)1.1)质膜表达所必需的，可能是通过与β调节亚基的相互作用实现的。因此，AHNAK1通过激活TCR激活的Ca(V)1通道在T细胞钙信号转导中发挥重要作用；因此，AHNAK1是一个潜在的治疗干预靶点。
Engagement of the T cell antigen receptor (TCR) during antigen presentation initiates a coordinated action of a large number of signaling proteins and ion channels. AHNAK1 is a scaffold protein, highly expressed by CD4(+) T cells, and is a critical component for calcium signaling. We showed that AHNAK1-deficient mice were highly susceptible to Leishmania major infection. AHNAK1-deficient CD4(+) T cells responded poorly to TCR stimulation in vitro with low proliferation and low Interleukin-2 production. Furthermore, AHNAK1 deficiency resulted in a reduced calcium influx upon TCR crosslinking and subsequent poor activation of the transcription factor NFAT. AHNAK1 was required for plasma membrane expression of L-type calcium channels alpha 1S (Ca(v)1.1), probably through its interaction with the beta regulatory subunit. Thus, AHNAK1 plays an essential role in T cell Ca2+ signaling through Ca(v)1 channels, triggered via TCR activation; therefore, AHNAK1 is a potential target for therapeutic intervention.