Department of Microbiology & Immunology, University of Iowa, Iowa City, Iowa, USA; Immunology Graduate Program, University of Iowa, Iowa City, Iowa, USA; Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, USA; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, USA.
Department of Microbiology & Immunology, University of Iowa, Iowa City, Iowa, USA; Immunology Graduate Program, University of Iowa, Iowa City, Iowa, USA.
J Biol Chem. 2021 Jan-Jun;296:100465. doi: 10.1016/j.jbc.2021.100465. Epub 2021 Feb 25.
TRAF3 has diverse signaling functions, which vary by cell type. Uniquely in B lymphocytes, TRAF3 inhibits homeostatic survival. Highlighting the role of TRAF3 as a tumor suppressor, loss-of-function TRAF3 mutations are associated with human B-cell malignancies, while B-cell-specific deletion of TRAF3 in mice leads to autoimmunity and lymphoma development. The role of TRAF3 in inhibiting noncanonical NF-κB activation, CD40 and BAFF-R signaling to B cells is well documented. In contrast, TRAF3 enhances many T-cell effector functions, through associating with and enhancing signaling by the T-cell receptor (TCR)-CD28 complex. The present study was designed to determine the role of TRAF3 in signaling via the B-cell antigen receptor (BCR). The BCR is crucial for antigen recognition, survival, proliferation, and antibody production, and defects in BCR signaling can promote abnormal survival of malignant B cells. Here, we show that TRAF3 is associated with both CD79B and the BCR-activated kinases Syk and Btk following BCR stimulation. BCR-induced phosphorylation of Syk and additional downstream kinases was increased in TRAF3 B cells, with regulation observed in both follicular and marginal zone B-cell subsets. BCR stimulation of TRAF3 B cells resulted in increased surface expression of MHC-II, CD80, and CD86 molecules. Interestingly, increased survival of TRAF3 primary B cells was resistant to inhibition of Btk, while TRAF3-deficient malignant B-cell lines showed enhanced sensitivity. TRAF3 serves to restrain normal and malignant BCR signaling, with important implications for its role in normal B-cell biology and abnormal survival of malignant B cells.
TRAF3 具有多种信号功能，这些功能因细胞类型而异。在 B 淋巴细胞中，TRAF3 独特地抑制稳态存活。突出了 TRAF3 作为肿瘤抑制因子的作用，功能丧失的 TRAF3 突变与人类 B 细胞恶性肿瘤相关，而小鼠中 B 细胞特异性的 TRAF3 缺失导致自身免疫和淋巴瘤的发展。TRAF3 在抑制非典型 NF-κB 激活、CD40 和 BAFF-R 信号转导至 B 细胞中的作用已有充分的文献记载。相比之下，TRAF3 通过与 T 细胞受体 (TCR)-CD28 复合物结合并增强其信号转导，增强了许多 T 细胞效应功能。本研究旨在确定 TRAF3 在 B 细胞抗原受体 (BCR) 信号转导中的作用。BCR 对于抗原识别、存活、增殖和抗体产生至关重要，BCR 信号转导缺陷可促进恶性 B 细胞的异常存活。在这里，我们表明，BCR 刺激后，TRAF3 与 CD79B 和 BCR 激活的激酶 Syk 和 Btk 相关。TRAF3 细胞中 BCR 诱导的 Syk 和其他下游激酶的磷酸化增加，在滤泡和边缘区 B 细胞亚群中均观察到调节作用。TRAF3 细胞的 BCR 刺激导致 MHC-II、CD80 和 CD86 分子的表面表达增加。有趣的是，TRAF3 原代 B 细胞的存活增加对 Btk 抑制具有抗性，而 TRAF3 缺陷的恶性 B 细胞系则表现出增强的敏感性。TRAF3 可抑制正常和恶性 BCR 信号转导，这对其在正常 B 细胞生物学和恶性 B 细胞异常存活中的作用具有重要意义。
