Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases.

中文翻译：

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UHRF1P 通过 UHRF1-MAP4K3 轴促进 IL-17A 介导的系统性红斑狼疮

炎症性 T 细胞参与系统性红斑狼疮 (SLE) 等自身免疫性疾病的发病机制。通过三个机器学习模型对两个独立 SLE 患者队列的 T 细胞转录组数据进行分析，揭示了假基因 UHRF1P 作为一种新型 SLE 生物标志物。假基因编码的 UHRF1P 蛋白在 SLE 患者的外周血 T 细胞中过度表达。 UHRF1P 蛋白缺乏其亲本 UHRF1 蛋白的氨基末端，导致缺失 UHRF1 的蛋白酶体结合泛素样 (Ubl) 结构域。 T 细胞特异性 UHRF1P 转基因小鼠表现出 IL-17A 和自身免疫炎症的诱导。从机制上讲，UHFR1P 阻止了 UHRF1 诱导的 Lys48 连接的泛素化和 MAP4K3 (GLK) 的降解，MAP4K3 (GLK) 是一种已知诱导 IL-17A 的激酶。一致地，UHRF1P 转基因小鼠的 IL-17A 诱导和自身免疫表型被 MAP4K3 敲除所消除。总的来说，T 细胞中 UHRF1P 的过度表达会抑制其亲本 UHRF1 的 E3 连接酶功能，并诱发自身免疫性疾病。