School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China.
Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E4051-E4060. doi: 10.1073/pnas.1801340115. Epub 2018 Apr 9.
Despite decades of research, mechanisms controlling T cell activation remain only partially understood, which hampers T cell-based immune cancer therapies. Here, we performed a genome-wide CRISPR screen to search for genes that regulate T cell activation. Our screen confirmed many of the known regulators in proximal T cell receptor signaling and, importantly, also uncovered a previously uncharacterized regulator, FAM49B (family with sequence similarity 49 member B). FAM49B deficiency led to hyperactivation of Jurkat T cells following T cell receptor stimulation, as indicated by enhancement of CD69 induction, PAK phosphorylation, and actin assembly. FAM49B directly interacted with the active form of the small GTPase Rac, and genetic disruption of the FAM49B-Rac interaction compromised FAM49B function. Thus, FAM49B inhibits T cell activation by repressing Rac activity and modulating cytoskeleton reorganization.
尽管已经进行了几十年的研究，但控制 T 细胞激活的机制仍仅部分得到了解，这阻碍了基于 T 细胞的免疫癌症疗法的发展。在这里，我们进行了全基因组 CRISPR 筛选，以寻找调节 T 细胞激活的基因。我们的筛选证实了 T 细胞受体信号转导中许多已知的调节剂，重要的是，还发现了一个以前未被表征的调节剂 FAM49B（家族与序列相似性 49 成员 B）。FAM49B 缺陷导致 Jurkat T 细胞在 T 细胞受体刺激后过度激活，这表现为 CD69 诱导、PAK 磷酸化和肌动蛋白组装的增强。FAM49B 与小 GTPase Rac 的活性形式直接相互作用，FAM49B-Rac 相互作用的遗传破坏削弱了 FAM49B 的功能。因此，FAM49B 通过抑制 Rac 活性和调节细胞骨架重排来抑制 T 细胞激活。
