Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Proc Natl Acad Sci U S A. 2022 Sep 6;119(36):e2205629119. doi: 10.1073/pnas.2205629119. Epub 2022 Aug 29.
Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance.
消除自身反应性发育中的 B 细胞是防止产生自身抗体的重要机制。然而，BCR 信号如何触发未成熟 B 细胞凋亡仍知之甚少。我们发现，BCR 刺激可上调溶酶体相关跨膜蛋白 5（LAPTM5）的表达，LAPTM5 通过两种途径触发未成熟 B 细胞凋亡。LAPTM5 导致 BCR 内化，从而减少 SYK 和 ERK 的磷酸化。此外，LAPTM5 将 E3 泛素连接酶 WWP2 作为靶标进行溶酶体降解，导致其底物 PTEN 的积累。升高的 PTEN 水平抑制 AKT 磷酸化，导致 FOXO1 表达增加和细胞周期抑制剂 p27Kip1 和促凋亡分子 BIM 的上调。在体内，LAPTM5 参与自身反应性 B 细胞的清除，其缺失会加剧自身抗体的产生。我们的结果揭示了一种以前未被识别的机制，有助于未成熟 B 细胞凋亡和 B 细胞耐受。
