β-arrestin 2 quenches TLR signaling to facilitate the immune evasion of EPEC
β-arrestin 2 quenches TLR signaling to facilitate the immune evasion of EPEC
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beta-arrestin 2 淬灭 TLR 信号传导以促进 EPEC 的免疫逃避
DOI：
10.1080/19490976.2020.1759490
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发表时间：
2020-05-15
期刊：
影响因子：
12.2
通讯作者：
Yan, Dapeng
中科院分区：
文献类型：
--
作者：
Chen, Zijuan;Zhou, Ruixue;Yan, Dapeng
来自肠致病性大肠杆菌的蛋白质易位的内膜受体（Tir）与宿主细胞免疫受体基于酪氨酸的抑制基序（ITIM）共享序列相似性。TIR的ITIM是TIR介导的免疫抑制和逃避宿主免疫应答所必需的。然而，Tir调节免疫抑制的潜在分子机制仍不清楚。在这里，我们证明了β-arrestin 2，这是参与G蛋白偶联受体（GPCR）信号通路，与TIR的ITIM依赖性的方式相互作用。对于分子机制，我们发现β-arrestin 2增强了SHP-1向Tir的募集。募集的SHP-1通过在Tyr 288处去磷酸化TRAF 6来抑制K63连接的TRAF 6泛素化，并且通过在Tyr 206处去磷酸化TAK 1来抑制K63连接的TAK 1泛素化和磷酸化，从而切断下游信号传导和随后的细胞因子产生。此外，在β-arrestin 2缺陷小鼠和巨噬细胞中，Tir对免疫应答的抑制作用减弱。这些发现表明，β-arrestin 2是TIR介导的免疫逃避的关键调节因子，这可能成为细菌感染性疾病的新治疗靶点。
The protein translocated intimin receptor (Tir) from enteropathogenic Escherichia coli shares sequence similarity with the host cellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). The ITIMs of Tir are required for Tir-mediated immune inhibition and evasion of host immune responses. However, the underlying molecular mechanism by which Tir regulates immune inhibition remains unclear. Here we demonstrated that beta-arrestin 2, which is involved in the G-protein-coupled receptor (GPCR) signal pathway, interacted with Tir in an ITIM-dependent manner. For the molecular mechanism, we found that beta-arrestin 2 enhanced the recruitment of SHP-1 to Tir. The recruited SHP-1 inhibited K63-linked ubiquitination of TRAF6 by dephosphorylating TRAF6 at Tyr288, and inhibited K63-linked ubiquitination and phosphorylation of TAK1 by dephosphorylating TAK1 at Tyr206, which cut off the downstream signal transduction and subsequent cytokine production. Moreover, the inhibitory effect of Tir on immune responses was diminished in beta-arrestin 2-deficient mice and macrophages. These findings suggest that beta-arrestin 2 is a key regulator in Tir-mediated immune evasion, which could serve as a new therapeutic target for bacterial infectious diseases.