Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy.
Putting on the Brakes: Regulatory Kinases and Phosphatases Maintaining B Cell Anergy.
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DOI：
10.3389/fimmu.2018.00665
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发表时间：
2018
影响因子：
7.3
通讯作者：
Cambier JC
中科院分区：
文献类型：
--
作者：
Franks SE;Cambier JC
B细胞抗原受体（BCR）信号是一个受到正、负介质/调节因子严格调控的过程，以确保对外源和自身抗原的适当反应。当naïve B细胞识别抗原CD79 （BCR中含有免疫受体酪氨酸激活基元（ITAM）的信号亚基）时，CD79被磷酸化并招募Src和Syk家族激酶，然后磷酸化与下游激活信号通路相关的近端中间体。这种质膜定位信号体激活PI3K，导致PIP3的产生，PIP3对于膜定位和plecktrin同源结构域效应物的激活至关重要。相反，在无能B细胞中，慢性抗原刺激驱动CD79 ITAMs的偏倚单磷酸化，导致Lyn募集，而不是Syk募集，后者仅与双磷酸化ITAMs对接。在这种情况下，Lyn似乎主要作为抑制性信号通路的驱动因素，促进肌醇磷酸酶、SHIP-1和PTEN对PI3K通路的抑制，这些酶将PIP3水解为PIP2。Lyn也可能通过募集SHP-1（一种酪氨酸磷酸酶，可使激活信号分子去磷酸化）对信号传导进行负调控。编码或调节该轴组分表达的基因等位基因，包括SHIP-1、SHP-1、Csk/PTPn22和Lyn，已被证明具有自身免疫的风险。这篇综述将讨论这一途径的组成部分的功能相互作用以及风险等位基因对其功能的影响。
B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the BCR] is phosphorylated and recruits Src and Syk family kinases that then phosphorylate proximal intermediaries linked to downstream activating signaling circuitry. This plasma membrane localized signalosome activates PI3K leading to generation of PIP3 critical for membrane localization and activation of plecktrin homology domain-containing effectors. Conversely, in anergic B cells, chronic antigen stimulation drives biased monophosphorylation of CD79 ITAMs leading to recruitment of Lyn, but not Syk, which docks only to bi-phosphorylated ITAMS. In this context, Lyn appears to function primarily as a driver of inhibitory signaling pathways promoting the inhibition of the PI3K pathway by inositol phosphatases, SHIP-1 and PTEN, which hydrolyze PIP3 to PIP2. Lyn may also exert negative regulation of signaling through recruitment of SHP-1, a tyrosine phosphatase that dephosphorylates activating signaling molecules. Alleles of genes that encode or regulate expression of components of this axis, including SHIP-1, SHP-1, Csk/PTPn22, and Lyn, have been shown to confer risk of autoimmunity. This review will discuss functional interplay of components of this pathway and the impact of risk alleles on its function.