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首页> 外文期刊>Molecular and Cellular Biology >mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion
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mTOR Activation Promotes Plasma Cell Differentiation and Bypasses XBP-1 for Immunoglobulin Secretion

机译：mTOR激活促进血浆细胞分化并绕过XBP-1的免疫球蛋白分泌

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Plasma cells (PCs) are responsible for the secretion of antibodies. The development of fully functional PCs relies on the activation of the inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP-1) arm of the unfolded protein response (UPR). XBP-1-deficient PCs secrete antibodies poorly and exhibit distensions of the endoplasmic reticulum (ER). The kinase mammalian target of rapamycin (mTOR) promotes anabolic activities and is negatively regulated by the tuberous sclerosis complex (TSC). Deletion of TSC1 renders mTOR hyperactive. To explore the relationship between mTOR and the UPR in PC development and function, mice with conditional deletions of XBP-1 and/or TSC1 in their B cell lineage were generated. Deletion of TSC1 enhanced Ig synthesis and promoted differentiation into PCs independently of XBP-1, as evidenced by comparison of TSC1/XBP-1 double-knockout (DKO) PCs to XBP-1 knockout (KO) PCs. The typical morphological abnormalities of the ER in XBP-1 KO PCs were alleviated in the DKO PCs. Expression profiling identified the glycoprotein Ly6C as an mTOR target. Ly6C expression contributed to the enhanced Ig secretion from DKO PCs. Our data reveal a functional overlap between mTOR and the UPR in promoting PC development. In addition to the classical mTOR role in promoting protein synthesis, the mechanism entails transcription regulation of accessory molecules, such as Ly6C.
机译：浆细胞（PC）负责抗体的分泌。功能齐全的PC的开发依赖于未折叠蛋白应答（UPR）的需要肌醇的酶1 / X-box结合蛋白1（IRE1 / XBP-1）的激活。缺乏XBP-1的PC分泌的抗体较弱，并表现出内质网（ER）的膨胀。雷帕霉素的激酶哺乳动物靶标（mTOR）促进合成代谢活性，并由结节性硬化复合物（TSC）负调节。 TSC1的删除使mTOR活跃。为了探索mTOR和UPR在PC发育和功能之间的关系，生成了在其B细胞谱系中有条件缺失XBP-1和/或TSC1的小鼠。 TSC1 / XBP-1双敲除（DKO）PC与XBP-1敲除（KO）PC的比较证明了TSC1的缺失增强了Ig的合成并促进了PC的独立于XBP-1的分化。 DKO PC缓解了XBP-1 KO PC中ER的典型形态异常。表达谱鉴定糖蛋白Ly6C为mTOR靶标。 Ly6C表达有助于增强DKO PC的Ig分泌。我们的数据揭示了mTOR和UPR在促进PC开发方面的功能重叠。除了经典的mTOR在促进蛋白质合成中的作用外，该机制还需要辅助分子（如Ly6C）的转录调控。

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