Division of Rheumatology, Department of Medicine, Seoul St. Mary's Hospital, Catholic University, Seoul 06591, Korea.
Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea.
Cells. 2021 Dec 29;11(1):105. doi: 10.3390/cells11010105.
Ubiquitination is a crucial mechanism in regulating the immune response, setting the balance between immunity and tolerance. Here, we investigated the function of a poorly understood alternative branch of the ubiquitin-activating E1 enzyme UBA6 in activating immune cells. UBA6 expression levels were elevated in T cells by toll-like receptor agonists and anti-CD3/28 antibody stimulation, but not in dendritic cells, macrophages, B cells, and natural killer cells. Additionally, we generated T cell-specific UBA6-deficient mice and found that UBA6-deficient CD4 and CD8 T cells elevated the production of interferon-gamma (IFN-γ). Moreover, the transfer of UBA6-deficient CD4 and CD8 T cells in RAG1-knockout mice exacerbated the development of multi-organ inflammation compared with control CD4 and CD8 T cell transfer. In human peripheral blood CD4 and CD8 T cells, basal levels of UBA6 in lupus patients presented much lower than those in healthy controls. Moreover, the IFN-γ production efficiency of CD4 and CD8 T cells was negatively correlated to UBA6 levels in patients with lupus. Finally, we found that the function of UBA6 was mediated by destabilization of IκBα degradation, thereby increasing NF-κB p65 activation in the T cells. Our study identifies UBA6 as a critical regulator of IFN-γ production in T cells by modulating the NF-κB p65 activation pathway.
泛素化是调节免疫反应的关键机制，在免疫和耐受之间起着平衡作用。在这里，我们研究了泛素激活酶 E1 家族中一种了解甚少的替代分支 UBA6 在激活免疫细胞中的功能。T 细胞受到 Toll 样受体激动剂和抗 CD3/28 抗体刺激后，UBA6 的表达水平升高，但树突状细胞、巨噬细胞、B 细胞和自然杀伤细胞则不会。此外，我们构建了 T 细胞特异性 UBA6 缺陷小鼠，发现 UBA6 缺陷的 CD4 和 CD8 T 细胞会增加干扰素-γ（IFN-γ）的产生。此外，与对照 CD4 和 CD8 T 细胞转移相比，UBA6 缺陷的 CD4 和 CD8 T 细胞在 RAG1 敲除小鼠中转移会加剧多器官炎症的发展。在人类外周血 CD4 和 CD8 T 细胞中，狼疮患者的 UBA6 基础水平明显低于健康对照者。此外，狼疮患者 CD4 和 CD8 T 细胞的 IFN-γ产生效率与 UBA6 水平呈负相关。最后，我们发现 UBA6 的功能是通过 IκBα 降解的不稳定化来介导的，从而增加 T 细胞中 NF-κB p65 的激活。我们的研究确定 UBA6 是通过调节 NF-κB p65 激活途径来调节 T 细胞 IFN-γ产生的关键调节剂。
