TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity
TAPP Adaptors Control B Cell Metabolism by Modulating the Phosphatidylinositol 3-Kinase Signaling Pathway: A Novel Regulatory Circuit Preventing Autoimmunity
复制标题
DOI：
10.4049/jimmunol.1701440
复制
发表时间：
2018-07-15
影响因子：
4.4
通讯作者：
Marshall, Aaron J.
中科院分区：
文献类型：
--
作者：
Jayachandran, Nipun;Mejia, Edgard M.;Marshall, Aaron J.
I类PI 3 K酶通过磷酸化质膜脂质以产生两种不同的磷酸肌醇（PI）产物PI（3，4，5）P3和PI（3，4）P2，在B细胞活化中起关键作用。这些PI各自结合不同但重叠的细胞内蛋白质组，这些蛋白质组控制细胞存活、细胞骨架重组和代谢活性。含有PH结构域的串联蛋白（TAPP）以高特异性结合PI（3，4）P2，并且先前发现它们在TAPP敲入（KI）小鼠中与PI（3，4）P2的遗传解偶联导致慢性B细胞活化、异常生发中心（GC）和自身免疫。在这篇文章中，我们发现TAPPs提供反馈调节，影响PI 3 K信号和B细胞的代谢活化。活化后，TAPP KI B细胞显示出与细胞外酸化速率增加、葡萄糖转运蛋白GLUT 1表达增加和葡萄糖摄取增加相关的代谢活性增强。TAPP KI B细胞显示PI 3 K调节的激酶Akt、GSK 3 β和p70-S6 K的活化显著增加。相反，C-末端TAPP PH结构域在B细胞中的过表达可以通过需要TAPP PI（3，4）P2结合口袋的机制抑制Akt磷酸化。在TAPP KI B细胞中抑制PI 3 K通路降低GLUT 1表达和葡萄糖摄取，而单独抑制Akt不足以使这些反应正常化。TAPP KI GC B细胞也显示出GLUT 1和葡萄糖摄取增加，并且用糖酵解抑制剂2-脱氧-D-葡萄糖治疗减少了这些小鼠内的慢性GC应答和自身抗体产生。我们的研究结果表明，TAPP-PI（3，4）P2相互作用控制糖酵解的活化，并强调了该途径对B细胞活化，GC反应和自身免疫的重要性。
Class I PI3K enzymes play critical roles in B cell activation by phosphorylating plasma membrane lipids to generate two distinct phosphoinositide (PI) products, PI(3,4,5)P3 and PI(3,4)P2. These PIs each bind distinct but overlapping sets of intracellular proteins that control cell survival, cytoskeletal reorganization, and metabolic activity. The tandem PH domain containing proteins (TAPPs) bind with high specificity to PI(3,4)P2, and their genetic uncoupling from PI(3,4)P2 in TAPP knock in (KI) mice was previously found to cause chronic B cell activation, abnormal germinal centers (GCs), and autoimmunity. In this article, we find that TAPPs provide feedback regulation affecting PI3K signaling and metabolic activation of B cells. Upon activation, TAPP KI B cells show enhanced metabolic activity associated with increased extracellular acidification rate, increased expression of glucose transporter GLUT1, and increased glucose uptake. TAPP KI B cells show markedly increased activation of the PI3K-regulated kinases Akt, GSK3 beta, and p70-S6K. Conversely, overexpression of the C-terminal TAPP PH domains in B cells can inhibit Akt phosphorylation by a mechanism requiring the TAPP PI(3,4)P2-binding pocket. Inhibition of the PI3K pathway in TAPP KI B cells reduced GLUT1 expression and glucose uptake, whereas inhibition of Akt alone was not sufficient to normalize these responses. TAPP KI GC B cells also show increased GLUT1 and glucose uptake, and treatment with the inhibitor of glycolysis 2-deoxy-D-glucose reduced chronic GC responses and autoantibody production within these mice. Our findings show that TAPP-PI(3,4)P2 interaction controls activation of glycolysis and highlights the significance of this pathway for B cell activation, GC responses, and autoimmunity.