As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell–specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk) and phosphorylated SH2-containing inositol phosphatase (pSHIP), are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin) is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.

作为代谢机制的中心枢纽，雷帕霉素复合物2（mTORC2）的哺乳动物靶标已在淋巴细胞中进行了深入研究。作为mTORC2的强制性组成部分，Rictor在T细胞中的作用已得到充分确立。但是，Rictor在B细胞中的作用仍然难以捉摸。Rictor参与了B细胞的发育，尤其是外周细胞的发育。但是，Rictor对B细胞受体（BCR）信号传导的作用以及潜在的细胞和分子机制仍是未知的。这项研究使用了特定于B细胞的Rictor基因敲除（KO）小鼠来研究Rictor如何调节BCR信号传导。我们发现，在Rictor KO B细胞中，关键的阳性和阴性BCR信号分子，磷酸化的Brutons酪氨酸激酶（pBtk）和磷酸化的含SH2的肌醇磷酸酶（pSHIP）均被降低和增强。这表明Rictor积极调节BCR信号传导的早期事件。我们发现在BCR刺激后，Rictor KO B细胞中的细胞丝状肌动蛋白（F-肌动蛋白）急剧增加，这是由于ezrin的去磷酸化失调所致。高肌动蛋白-ezrin强度区域在刺激时限制了BCR的横向移动，因此减少了BCR簇和BCR信号传导。由肌动蛋白改变引起的BCR信号启动的减少与Rictor KO小鼠体内的体液免疫反应降低有关。Rictor KO B细胞中用latrunculin抑制肌动蛋白聚合可挽救BCR信号传导和B细胞分化的缺陷。总的来说，我们的研究提供了一条将细胞代谢与BCR激活联系起来的新途径，其中Rictor通过肌动蛋白重组来调节BCR信号传导。