Department of Biochemistry, University of Lausanne, Ch. des Boveresses 155, 1066 Epalinges, Switzerland; Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany; Medical Physics Department, Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Avenida E- Bustillo 9500, R8402AGP Río Negro, San Carlos de Bariloche, Argentina.
Faculty of Medicine and Medical Center, University of Freiburg, Department of Rheumatology and Center for Chronic Immunodeficiency, Breisacherstr. 115, 79106 Freiburg, Germany.
Cell Rep. 2022 Mar 29;38(13):110583. doi: 10.1016/j.celrep.2022.110583.
In mature B cells, TACI controls class-switch recombination and differentiation into plasma cells during T cell-independent antibody responses. TACI binds the ligands BAFF and APRIL. Approximately 10% of patients with common variable immunodeficiency (CVID) carry TACI mutations, of which A181E and C172Y are in the transmembrane domain. Residues A181 and C172 are located on distinct sides of the transmembrane helix, which is predicted by molecular modeling to spontaneously assemble into trimers and dimers. In human B cells, these mutations impair ligand-dependent (C172Y) and -independent (A181E) TACI multimerization and signaling, as well as TACI-enhanced proliferation and/or IgA production. Genetic inactivation of TACI in primary human B cells impaired survival of CpG-activated cells in the absence of ligand. These results identify the transmembrane region of TACI as an active interface for TACI multimerization in signal transduction, in particular for ligand-independent signals. These functions are perturbed by CVID-associated mutations.
在成熟的 B 细胞中，TACI 控制 T 细胞非依赖性抗体应答期间的类别转换重组和向浆细胞分化。TACI 结合配体 BAFF 和 APRIL。约 10%的常见可变免疫缺陷（CVID）患者携带 TACI 突变，其中 A181E 和 C172Y 在跨膜域中。残基 A181 和 C172 位于跨膜螺旋的不同侧，分子建模预测它们会自发组装成三聚体和二聚体。在人类 B 细胞中，这些突变会损害配体依赖性（C172Y）和非依赖性（A181E）TACI 多聚化和信号转导，以及 TACI 增强的增殖和/或 IgA 产生。在没有配体的情况下，CpG 激活的细胞中，TACI 在原发性人类 B 细胞中的遗传失活会损害细胞的存活。这些结果确定了 TACI 的跨膜区域是信号转导中 TACI 多聚化的活性界面，特别是对于非配体依赖性信号。这些功能被 CVID 相关突变所破坏。
