Wang Hua, Concannon Patrick, Ge Yan
International Center for Genetic Engineering and Biotechnology, China Regional Research Center, Taizhou, Jiangsu Province, China.
Genetics Institute, University of Florida, Gainesville, FL, USA.
Genes Immun. 2025 Feb;26(1):54-62. doi: 10.1038/s41435-024-00300-8. Epub 2024 Nov 18.
The T cell Ubiquitin Ligand (TULA) protein family contains two members, UBASH3A and UBASH3B, that display similarities in protein sequence and domain structure. Both TULA proteins act to repress T cell activation via a combination of overlapping and nonredundant functions. UBASH3B acts mainly as a phosphatase that suppresses proximal T cell receptor (TCR) signaling. In contrast, UBASH3A acts primarily as an adaptor protein, interacting with other proteins (including UBASH3B) in T cells upon TCR stimulation and resulting in downregulation of TCR signaling and NF-κB signaling. Human genetic and functional studies have revealed another notable distinction between UBASH3A and UBASH3B: numerous genome-wide association studies have identified statistically significant associations between genetic variants in and around the UBASH3A gene and at least seven different autoimmune diseases, suggesting a key role of UBASH3A in autoimmunity. However, the evidence for an independent role of UBASH3B in autoimmune disease is limited. This review summarizes key findings regarding the roles of TULA proteins in T cell biology and autoimmunity, highlights the commonalities and differences between UBASH3A and UBASH3B, and speculates on the individual and joint effects of TULA proteins on T cell signaling.
T细胞泛素配体（TULA）蛋白家族包含两个成员，即UBASH3A和UBASH3B，它们在蛋白质序列和结构域结构上显示出相似性。两种TULA蛋白都通过重叠和非冗余功能的组合来抑制T细胞活化。UBASH3B主要作为一种磷酸酶，抑制近端T细胞受体（TCR）信号传导。相比之下，UBASH3A主要作为一种衔接蛋白，在TCR刺激后与T细胞中的其他蛋白（包括UBASH3B）相互作用，导致TCR信号传导和NF-κB信号传导的下调。人类遗传学和功能研究揭示了UBASH3A和UBASH3B之间的另一个显著区别：大量全基因组关联研究已经确定UBASH3A基因及其周围的遗传变异与至少七种不同的自身免疫性疾病之间存在统计学上的显著关联，这表明UBASH3A在自身免疫中起关键作用。然而，关于UBASH3B在自身免疫性疾病中独立作用的证据有限。这篇综述总结了关于TULA蛋白在T细胞生物学和自身免疫中作用的关键发现，强调了UBASH3A和UBASH3B之间的共性和差异，并推测了TULA蛋白对T细胞信号传导的个体和联合作用。
