School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
R&D center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Daejeon, Republic of Korea.
FASEB J. 2021 Apr;35(4):e21479. doi: 10.1096/fj.202002325RR.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface receptor expressed on macrophages, microglial cells, and pre-osteoclasts, and that participates in diverse cellular function, including inflammation, bone homeostasis, neurological development, and coagulation. In spite of the indispensable role of the TREM2 protein in the maintenance of immune homeostasis and osteoclast differentiation, the exact ligand for TREM2 has not yet been identified. Here, we report a putative TREM2 ligand which is secreted from MC38 cells and identified as a cyclophilin A (CypA). A specific interaction between CypA and TREM2 was shown at both protein and cellular levels. Exogenous CypA specifically interacted and co-localized with TREM2 in RAW264.7 cells, and the physical interactions were shown to regulate TREM2 signaling transduction. The Pro residue in the extracellular domain of TREM2 was found to be the specific binding site of CypA. When considered together, this provides evidence that CypA interacts specifically with TREM2 as a potent ligand.
髓系细胞触发受体 2（TREM2）是一种表达于巨噬细胞、小神经胶质细胞和破骨前体细胞表面的细胞表面受体，参与多种细胞功能，包括炎症、骨稳态、神经发育和凝血。尽管 TREM2 蛋白在维持免疫稳态和破骨细胞分化方面起着不可或缺的作用，但 TREM2 的确切配体尚未确定。在这里，我们报告了一种可能的 TREM2 配体，它是从 MC38 细胞分泌的，并被鉴定为亲环素 A（CypA）。在蛋白质和细胞水平上都显示出 CypA 与 TREM2 之间的特异性相互作用。外源性 CypA 特异性地与 RAW264.7 细胞中的 TREM2 相互作用和共定位，并且显示出物理相互作用调节 TREM2 信号转导。在 TREM2 的细胞外结构域中发现脯氨酸残基是 CypA 的特异性结合位点。总的来说，这提供了证据表明 CypA 作为一种有效的配体与 TREM2 特异性相互作用。
