Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; and National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; and National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
J Immunol. 2020 Mar 15;204(6):1535-1542. doi: 10.4049/jimmunol.1901156. Epub 2020 Jan 31.
Mature naive B cells expressing BCRs of the IgM and IgD isotypes respond to Ag in secondary lymphoid organs. However, the vast majority of B cells do not undergo productive Ag encounter and have finite life spans dependent on survival signals propagated by the BCR and the BAFFR. In this study, we show that the E3 ubiquitin ligase Fbw7 is required for the maintenance of mature B cell populations in mice. BCR stimulation of B cells induced substantial apoptosis along with proliferative and growth defects upon the loss of Fbw7. Analysis of B cell proteomes revealed aberrant signaling patterns, including lower Bcl2 and diminished NF-κB signaling. Further, excessive accumulation of Fbw7 substrate c-Myc, increased Bim expression, and loss of PI3K signaling mediated apoptosis downstream of BCR signaling. In accordance, strong prosurvival signals delivered through ectopic expression of BCL2 in B cells could largely rescue apoptotic cells in the absence of Fbw7. Overall, this study reveals an unexpected role for Fbw7 in the survival and fitness of mature B cells.
表达 IgM 和 IgD 同种型 BCR 的成熟幼稚 B 细胞在次级淋巴器官中对 Ag 作出反应。然而，绝大多数 B 细胞不会经历有性 Ag 遭遇，并且其寿命取决于由 BCR 和 BAFFR 传播的存活信号。在这项研究中，我们表明 E3 泛素连接酶 Fbw7 对于维持小鼠成熟 B 细胞群体是必需的。BCR 刺激 B 细胞在 Fbw7 缺失时诱导大量凋亡，同时伴有增殖和生长缺陷。B 细胞蛋白质组分析显示出异常的信号模式，包括 Bcl2 降低和 NF-κB 信号减弱。此外，Fbw7 底物 c-Myc 的过度积累、Bim 表达增加以及 PI3K 信号的丧失介导了 BCR 信号下游的细胞凋亡。相应地，通过在 B 细胞中异位表达 BCL2 传递的强烈的生存信号可以在没有 Fbw7 的情况下很大程度上挽救凋亡细胞。总的来说，这项研究揭示了 Fbw7 在成熟 B 细胞的存活和适应性中的意外作用。
