Departments of Pathology and Microbiology & Pathology, Vanderbilt University School of Medicine, Nashville, TN;
Blood. 2013 Oct 3;122(14):2369-79. doi: 10.1182/blood-2013-01-477505. Epub 2013 Aug 19.
The mammalian target of rapamycin (mTOR), an essential serine/threonine kinase, functions in biochemically distinct multiprotein complexes, but little is known about roles of the complexes in B cells. The acutely rapamycin-sensitive mTOR complex 1 (mTORC1) is defined by a core subunit Raptor, whereas mTORC2 lacks Raptor and, instead, has Rictor and SIN1 as distinct essential components. We now show that homeostasis and function of B cells require Rictor. Conditional deletion of Rictor before lymphoid specification impaired generation of mature follicular, marginal zone, and B1a B lymphocytes. Induced inactivation in adult mice caused cell-autonomous defects in B lymphoid homeostasis and antibody responses in vivo, along with affecting plasma cells in bone marrow. Survival of B lymphocytes depended on Rictor, which was vital for normal induction of prosurvival genes, suppression of proapoptotic genes, nuclear factor κB induction after B-cell receptor stimulation, and B-cell activating factor-induced nuclear factor κB2/p52 generation. Collectively, the findings provide evidence that mTOR signaling affects survival and proliferation of mature B lymphocytes, and establish Rictor as an important signal relay in B-cell homeostasis, fate, and functions.
哺乳动物雷帕霉素靶蛋白（mTOR）是一种必需的丝氨酸/苏氨酸激酶，它在生化上不同的多蛋白复合物中发挥作用，但关于复合物在 B 细胞中的作用知之甚少。急性雷帕霉素敏感的 mTOR 复合物 1（mTORC1）由核心亚基 Raptor 定义，而 mTORC2 缺乏 Raptor，而是具有 Rictor 和 SIN1 作为独特的必需成分。我们现在表明，B 细胞的稳态和功能需要 Rictor。在淋巴样分化前条件性删除 Rictor 会损害成熟滤泡、边缘区和 B1a B 淋巴细胞的生成。在成年小鼠中诱导失活会导致体内 B 淋巴样稳态和抗体反应的细胞自主缺陷，同时影响骨髓中的浆细胞。B 淋巴细胞的存活依赖于 Rictor，它对正常诱导生存基因、抑制促凋亡基因、B 细胞受体刺激后核因子 κB 的诱导以及 B 细胞激活因子诱导的核因子 κB2/p52 的产生至关重要。总之，这些发现提供了证据表明 mTOR 信号影响成熟 B 淋巴细胞的存活和增殖，并确立了 Rictor 作为 B 细胞稳态、命运和功能中重要的信号转导蛋白。
