Institute of Immunity and Transplantation, The Pears Building, University College London, London, United Kingdom.
Vlaams Instituut voor Biotechnologie (VIB) Center for Inflammation Research, Ghent, Belgium.
Front Immunol. 2022 Dec 1;13:1067164. doi: 10.3389/fimmu.2022.1067164. eCollection 2022.
The Inhibitor of Kappa B Kinase (IKK) complex is a critical regulator of NF-κB activation. More recently, IKK has also been shown to repress RIPK1 dependent extrinsic cell death pathways by directly phosphorylating RIPK1 at serine 25. In T cells, IKK expression is essential for normal development in the thymus, by promoting survival of thymocytes independently of NF-κB activation. RIPK1 undergoes extensive phosphorylation following TNF stimulation in T cells, though which targets are required to repress RIPK1 has not been defined. Here, we show that TNF induced phosphorylation of RIPK1 at S25 is IKK dependent. We test the relevance of this phosphorylation event in T cells using mice with a RIPK1 phosphomimetic point mutation to endogenous RIPK1. We find that this mutation protects T cells from TNF induced cell death when IKK activity is inhibited , and can rescues development of IKK deficient thymocytes to a degree comparable with kinase dead RIPK1. Together, these data show that phosphorylation of RIPK1S25 by IKK represents a key regulatory event promoting survival of T cells by IKK.
IKK 激酶（IKK）复合物是 NF-κB 激活的关键调节剂。最近，研究还表明 IKK 通过直接在丝氨酸 25 位磷酸化 RIPK1 来抑制 RIPK1 依赖性的外在细胞死亡途径。在 T 细胞中，IKK 的表达对于胸腺中的正常发育是必需的，通过促进胸腺细胞的存活而不依赖于 NF-κB 的激活。在 T 细胞中，TNF 刺激后 RIPK1 会发生广泛的磷酸化，尽管目前还没有确定哪些靶点需要被抑制来抑制 RIPK1。在这里，我们表明 TNF 诱导的 RIPK1 在 S25 上的磷酸化依赖于 IKK。我们使用带有 RIPK1 磷酸模拟点突变的内源性 RIPK1 的小鼠来测试这一磷酸化事件在 T 细胞中的相关性。我们发现，当 IKK 活性被抑制时，这种突变可以保护 T 细胞免受 TNF 诱导的细胞死亡，并且可以在一定程度上拯救 IKK 缺陷的胸腺细胞的发育，与激酶失活的 RIPK1 相当。总之，这些数据表明，IKK 对 RIPK1S25 的磷酸化是 IKK 促进 T 细胞存活的关键调节事件。
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