Rictor positively regulates B cell receptor signaling by modulating actin reorganization via ezrin.
Rictor positively regulates B cell receptor signaling by modulating actin reorganization via ezrin.
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Rictor 通过埃兹蛋白调节肌动蛋白重组，从而正向调节 B 细胞受体信号传导。
DOI：
10.1371/journal.pbio.2001750
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发表时间：
2017-08
期刊：
影响因子：
9.8
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Huang L;Zhang Y;Xu C;Gu X;Niu L;Wang J;Sun X;Bai X;Xuan X;Li Q;Shi C;Yu B;Miller H;Yang G;Westerberg LS;Liu W;Song W;Zhao X;Liu C
哺乳动物雷帕霉素靶蛋白复合物2（mTORC 2）作为代谢机制的中心枢纽，在淋巴细胞中已得到充分研究。作为mTORC 2的一个强制性成分，Rictor在T细胞中的作用已得到充分证实。然而，Rictor在B细胞中的作用仍然是难以捉摸的。Rictor参与B细胞的发育，尤其是外周细胞的发育。然而，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然是未知的。本研究使用B细胞特异性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SH 2的肌醇磷酸酶（pSHIP）分别减少和增强。这表明Rictor正调控BCR信号传导的早期事件。我们发现BCR刺激后Rictor KO B细胞中细胞丝状肌动蛋白（F-actin）显著增加，这是由于ezrin去磷酸化的失调所致。高肌动蛋白-埃兹蛋白强度区域限制刺激后BCR的侧向运动，从而减少BCR聚集和BCR信号传导。肌动蛋白改变引起的BCR信号起始的减少与Rictor KO小鼠中体液免疫应答的降低有关。在Rictor KO B细胞中用latrunculin抑制肌动蛋白聚合挽救了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个新的途径连接细胞代谢BCR激活，其中Rictor调节BCR信号通过肌动蛋白重组。作为细胞代谢的中心枢纽，哺乳动物雷帕霉素靶蛋白复合物（mTORC）整合了免疫信号和代谢线索，以维持和激活这些系统。Rictor是雷帕霉素复合物2（mTORC 2）的哺乳动物靶标的核心组分，并且该蛋白质的缺失导致涉及（除其他外）受损的抗体产生的免疫缺陷。B细胞受体（BCR）信号传导对于抗体生成是关键的，尽管已经显示B细胞中Rictor的丧失对该功能产生负面影响，但潜在的分子机制尚不清楚。在这里，我们表明，早期和远端BCR信号减少Rictor敲除（KO）B细胞。我们发现BCR信号的减少源于早期B细胞活化过程中BCR的聚集缺陷。这似乎是由肌动蛋白连接蛋白ezrin的不受控制的激活引起的，这导致了一个刚性的肌动蛋白栅栏，限制了BCR在膜中的横向运动。有趣的是，用肌动蛋白抑制剂治疗Rictor KO小鼠拯救了BCR信号传导。我们的研究结果表明，Rictor有助于通过触发肌动蛋白网络的重组，从而在感染期间实现适当的抗体应答，从而在B细胞中实现有效的BCR信号传导。
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. As the central hub of cell metabolism, the mammalian target of rapamycin complex (mTORC) integrates immune signals and metabolic cues for the maintenance and activation of these systems. Rictor is the core component of the mammalian target of rapamycin complex 2 (mTORC2), and loss of this protein leads to an immunodeficiency that involves (among other things) impaired antibody production. B cell receptor (BCR) signaling is critical for antibody generation and although it has been shown that loss of Rictor in B cells negatively impacts this function, the underlying molecular mechanisms are unknown. Here, we show that both early and distal BCR signaling is reduced in Rictor knockout (KO) B cells. We find that the reduction in BCR signaling stems from defective clustering of BCRs during early B cell activation. This seems to be caused by the uncontrolled activation of the actin-connecting protein ezrin, which leads to a rigid actin fence that restricts the lateral movement of BCRs in the membrane. Interestingly, treatment of Rictor KO mice with an actin inhibitor rescues the BCR signaling. Our findings suggest that Rictor helps to allow effective BCR signaling in B cells by triggering reorganization of the actin network, thereby enabling an appropriate antibody response during infection.
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影响因子：
15.3
作者：
Fujikawa, K;Miletic, AV;Alt, FW;Faccio, R;Brown, T;Hoog, J;Fredericks, J;Nishi, S;Mildiner, S;Moores, SL;Brugge, J;Rosen, FS;Swat, W
通讯作者：
Swat, W
影响因子：
4.4
作者：
Li, Yansong;Harada, Tatsuhiro;Tsokos, George C.
通讯作者：
Tsokos, George C.
影响因子：
2.3
作者：
Jensen, PV;Larsson, LI
通讯作者：
Larsson, LI
DOI：
10.1083/jcb.200707199
发表时间：
2007-11-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ilani T;Khanna C;Zhou M;Veenstra TD;Bretscher A
通讯作者：
Bretscher A
影响因子：
9.8
作者：
Liu C;Bai X;Wu J;Sharma S;Upadhyaya A;Dahlberg CI;Westerberg LS;Snapper SB;Zhao X;Song W
通讯作者：
Song W