To mount an antipathogen response, CD4 T cells must undergo rapid cell proliferation; however, poorly controlled expansion can result in diseases such as autoimmunity. One important regulator of T‐cell activity is the E3 ubiquitin ligase Itch. Itch deficient patients suffer from extensive autoinflammation. Similarly, Itch deficient mice exhibit inflammation characterized by high numbers of activated CD4 T cells. While the role of Itch in limiting CD4 T‐cell cytokine production has been extensively studied, it is less clear whether and how Itch regulates proliferation of these cells. We determined that Itch deficient CD4 T cells are hyperproliferative in vitro and in vivo, due to increased S phase entry. Whole cell proteomics analysis of Itch deficient primary mouse CD4 T cells revealed increased abundance of the β‐catenin coactivator WW domain‐binding protein 2 (WBP2). Furthermore, Itch deficient cells demonstrate increased WBP2 protein stability, and Itch and WBP2 interact in CD4 T cells. Knockdown of WBP2 in CD4 T cells caused reduced proliferation. Together, our data support that Itch attenuates CD4 T cell proliferation by promoting WBP2 degradation. This study identifies novel roles for Itch and WBP2 in regulating CD4 T cell proliferation, providing insight into how Itch may prevent inflammation.

中文翻译：

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Itch 通过限制 WBP2 蛋白的稳定性来减弱小鼠的 CD4 T 细胞增殖。

为了产生抗病原体反应，CD4 T 细胞必须经历快速的细胞增殖；然而，控制不当的扩张会导致疾病，如自身免疫。T 细胞活性的一个重要调节因子是 E3 泛素连接酶 Itch。瘙痒不足的患者患有广泛的自身炎症。同样，Itch 缺陷小鼠表现出以大量活化 CD4 T 细胞为特征的炎症。虽然已经广泛研究了 Itch 在限制 CD4 T 细胞细胞因子产生方面的作用，但目前尚不清楚 Itch 是否以及如何调节这些细胞的增殖。我们确定 Itch 缺陷 CD4 T 细胞在体外和体内过度增殖，这是由于 S 期进入增加。对 Itch 缺陷的原代小鼠 CD4 T 细胞的全细胞蛋白质组学分析显示，β-连环蛋白辅激活因子 WW 结构域结合蛋白 2 (WBP2) 的丰度增加。此外，Itch 缺陷细胞表现出增加的 WBP2 蛋白稳定性，并且 Itch 和 WBP2 在 CD4 T 细胞中相互作用。CD4 T 细胞中 WBP2 的敲低导致增殖减少。总之，我们的数据支持 Itch 通过促进 WBP2 降解来减弱 CD4 T 细胞增殖。这项研究确定了 Itch 和 WBP2 在调节 CD4 T 细胞增殖方面的新作用，从而深入了解了 Itch 如何预防炎症。我们的数据支持 Itch 通过促进 WBP2 降解来减弱 CD4 T 细胞增殖。这项研究确定了 Itch 和 WBP2 在调节 CD4 T 细胞增殖方面的新作用，从而深入了解了 Itch 如何预防炎症。我们的数据支持 Itch 通过促进 WBP2 降解来减弱 CD4 T 细胞增殖。这项研究确定了 Itch 和 WBP2 在调节 CD4 T 细胞增殖方面的新作用，从而深入了解了 Itch 如何预防炎症。