LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway.

BCR cross-linking has been shown to trigger a signal transduction cascade that involves coordinated functions of kinases, adaptor molecules, and phosphatases. The present study demonstrates that BCR signaling in immature B cells is in part regulated by a lysosomal protein, LAPTM5. Our results uncover a previously unidentified LAPTM5-WWP2-PTEN cascade that regulates immature B cell apoptosis and contributes to B cell tolerance. 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.

BCR交联已被证明可触发一个信号转导级联反应，该反应涉及激酶、衔接分子和磷酸酶的协同作用。本研究表明，未成熟B细胞中的BCR信号传导部分受一种溶酶体蛋白LAPTM5的调控。我们的研究结果揭示了一个先前未被识别的LAPTM5 - WWP2 - PTEN级联反应，它调控未成熟B细胞的凋亡并有助于B细胞的耐受性。 清除自身反应性发育中的B细胞是防止自身抗体产生的一个重要机制。然而，B细胞受体（BCR）信号传导如何触发未成熟B细胞的凋亡仍知之甚少。我们发现BCR刺激会上调溶酶体相关跨膜蛋白5（LAPTM5）的表达，而LAPTM5反过来通过两条途径触发未成熟B细胞的凋亡。LAPTM5导致BCR内化，从而使SYK和ERK的磷酸化降低。此外，LAPTM5使E3泛素连接酶WWP2成为溶酶体降解的目标，导致其底物PTEN的积累。PTEN水平升高会抑制AKT磷酸化，从而导致FOXO1表达增加以及细胞周期抑制剂p27Kip1和促凋亡分子BIM的上调。在体内，LAPTM5参与清除自身反应性B细胞，其缺失会加剧自身抗体的产生。我们的研究结果揭示了一个先前未被识别的有助于未成熟B细胞凋亡和B细胞耐受性的机制。