Moon Jae-Seung, Lee Hong-Jai, Ho Chun-Chang, Shin Jin-Su, Ghosh Sankar, Kim Jung-Ho, Lee Sang-Kyou
Department of Biotechnology, Yonsei University College of Life Science and Biotechnology, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
Int J Hematol. 2018 Oct;108(4):375-383. doi: 10.1007/s12185-018-2491-6. Epub 2018 Jul 5.
The BAF57 subunit, an indispensable member of the BAF complex, is functionally implicated in apoptosis, cell cycle, and T cell development through chromosomal remodeling. However, the precise roles of BAF57 in the T cell receptor (TcR)-mediated signaling pathway have not been elucidated. In this study, a nucleus-transducible form of BAF57, absent the proline-rich and HMG domains (ntBAF57-ΔPH), was generated to interfere with the interaction between BAF57 and its binding protein, BAF155. ntBAF57-ΔPH was effectively delivered into mouse CD4 T cells in a dose- and time-dependent manner, without cellular toxicity. Inhibition of T cell activation by ntBAF57-ΔPH was mediated by its disruption of the interaction between BAF155 and BAF57, leading to the degradation of endogenous BAF57 and BAF155. This phenomenon led to alterations in gene expression similar to those associated with Ciclosporin A treatment. In vivo administration of ntBAF57-ΔPH enhanced survival rate of sepsis-induced mice and reduced the LPS-induced secretion of pro-inflammatory cytokines and the expression of endogenous BAF57. These results reveal a novel function of BAF57 as an essential regulator of T cell activation. ntBAF57-ΔPH represents a novel immune-suppressive drug candidate with potential uses in the treatment of autoimmunity and graft rejection.
BAF57亚基是BAF复合物中不可或缺的成员，通过染色体重塑在细胞凋亡、细胞周期和T细胞发育中发挥功能作用。然而，BAF57在T细胞受体（TcR）介导的信号通路中的具体作用尚未阐明。在本研究中，构建了一种缺失富含脯氨酸和HMG结构域的细胞核可转导形式的BAF57（ntBAF57-ΔPH），以干扰BAF57与其结合蛋白BAF155之间的相互作用。ntBAF57-ΔPH以剂量和时间依赖性方式有效地递送至小鼠CD4 T细胞中，且无细胞毒性。ntBAF57-ΔPH对T细胞活化的抑制作用是通过破坏BAF155与BAF57之间的相互作用介导的，导致内源性BAF57和BAF155降解。这种现象导致基因表达的改变，类似于环孢素A处理相关的改变。ntBAF57-ΔPH的体内给药提高了脓毒症诱导小鼠的存活率，并降低了脂多糖诱导的促炎细胞因子分泌和内源性BAF57的表达。这些结果揭示了BAF57作为T细胞活化的关键调节因子的新功能。ntBAF57-ΔPH代表一种新型免疫抑制药物候选物，在自身免疫和移植排斥治疗中具有潜在用途。
