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 β-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 β-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 β-arrestin 2-deficient mice and macrophages. These findings suggest that β-arrestin 2 is a key regulator in Tir-mediated immune evasion, which could serve as a new therapeutic target for bacterial infectious diseases.

来自肠致病性大肠杆菌的蛋白质易位intimin受体（Tir）与基于宿主细胞免疫受体酪氨酸的抑制基序（ITIM）具有序列相似性。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。但是，Tir调节免疫抑制的潜在分子机制仍然不清楚。在这里，我们证明了参与G蛋白偶联受体（GPCR）信号通路的β-arrestin2与Tir以ITIM依赖性方式相互作用。对于分子机理，我们发现β-arrestin2增强了SHP-1向Tir的募集。募集的SHP-1通过在Tyr288处使TRAF6磷酸化来抑制TRAF6的K63连接泛素化，并通过在Tyr206处TAK1进行磷酸化来抑制K63连接的泛素化和TAK1的磷酸化，切断了下游信号转导和后续细胞因子的产生。而且，在缺乏β-arrestin2的小鼠和巨噬细胞中，Tir对免疫反应的抑制作用减弱。这些发现表明，β-arrestin2是Tir介导的免疫逃逸的关键调节剂，可作为细菌感染性疾病的新治疗靶标。