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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hypoxia inducible factor 1α regulates T cell receptor signal transduction
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Hypoxia inducible factor 1α regulates T cell receptor signal transduction

机译：缺氧诱导因子1α调节T细胞受体信号转导

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摘要

Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1α. Here, we have examined the effect of Hif-1α, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1α under "normoxic" conditions, we achieved constitutive stabilization of Hif-1α through thymic deletion of Vhlh and reversed Hif-1α stabilization with double deletion of Vhlh and Hif-1α. We found that constitutive activity of Hif-1α resulted in diminished Ca~(2+) response upon TCR crosslinking despite equivalent activation of phospholipase C_(γ1), normal intracellular Ca~(2+) stores, and normal entry of Ca~(2+) across the plasma membrane. Altered Ca~(2+) response was instead due to accelerated removal of Ca~(2+) from the cytoplasm into intracellular compartments, which occurred in association with Hif-1α-depen-dent overexpression of the calcium pump SERCA2 (sarcoplasmic/ endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1α, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.
机译：低氧压存在于许多实体组织中，包括初级和次级淋巴器官。细胞适应缺氧的关键因素之一是诱导表达的缺氧诱导因子（Hif）1α。在这里，我们检查了Hif-1α（从无氧的其他多种影响中分离）对胸腺细胞中T细胞受体（TCR）信号的影响。因为pVHL（von Hippel-Lindau蛋白）在“常氧”条件下指导Hif-1α的蛋白水解，所以我们通过胸腺缺失Vhlh来实现Hif-1α的组成稳定，并通过重复删除Vhlh和Hif-1α来逆转Hif-1α的稳定作用。我们发现，尽管磷脂酶C_（γ1），正常的细胞内Ca〜（2+）储存和正常的Ca〜（2）激活相同，但Hif-1α的本构活性导致TCR交联后Ca〜（2+）的响应减弱。 +）穿过质膜。相反，改变的Ca〜（2+）反应是由于Ca〜（2+）从细胞质中加速移入细胞内区室，这与钙泵SERCA2的Hif-1α依赖性过表达有关（肌浆/内质网状钙ATPase 2）。这些数据提示了通过Hif-1α控制TCR信号传导的独特机制，该机制可能对实体淋巴器官中的生理氧张力起作用。

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