Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY; and.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
Immunohorizons. 2022 Nov 1;6(11):779-789. doi: 10.4049/immunohorizons.2100065.
Ets1 is a key transcription factor in B cells that is required to prevent premature differentiation into Ab-secreting cells. Previously, we showed that BCR and TLR signaling downregulate Ets1 levels and that the kinases PI3K, Btk, IKK, and JNK are required for this process. PI3K is important in activating Btk by generating the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate, to which Btk binds via its PH domain. Btk in turn is important in activating the IKK kinase pathway, which it does by activating phospholipase Cγ2→protein kinase Cβ signaling. In this study, we have further investigated the pathways regulating Ets1 in mouse B cells. Although IKK is well known for its role in activating the canonical NF-κB pathway, IKK-mediated downregulation of Ets1 does not require either RelA or c-Rel. We also examined the potential roles of two other IKK targets that are not part of the NF-κB signaling pathway, Foxo3a and mTORC2, in regulating Ets1. We find that loss of Foxo3a or inhibition of mTORC2 does not block BCR-induced Ets1 downregulation. Therefore, these two pathways are not key IKK targets, implicating other as yet undefined IKK targets to play a role in this process.
Ets1 是 B 细胞中的关键转录因子，它是防止过早分化为 Ab 分泌细胞所必需的。之前，我们表明 BCR 和 TLR 信号会下调 Ets1 水平，而 PI3K、Btk、IKK 和 JNK 激酶对于这个过程是必需的。PI3K 通过生成膜脂质磷脂酰肌醇（3,4,5）-三磷酸来激活 Btk，Btk 通过其 PH 结构域与该脂质结合。Btk 反过来又对激活 IKK 激酶途径很重要，它通过激活 PLCγ2→蛋白激酶 Cβ 信号来实现这一点。在这项研究中，我们进一步研究了调节小鼠 B 细胞中 Ets1 的途径。尽管 IKK 以其在激活经典 NF-κB 途径中的作用而闻名，但 IKK 介导的 Ets1 下调并不需要 RelA 或 c-Rel。我们还检查了不属于 NF-κB 信号通路的另外两个 IKK 靶标，Foxo3a 和 mTORC2，在调节 Ets1 中的潜在作用。我们发现 Foxo3a 的缺失或 mTORC2 的抑制并不阻止 BCR 诱导的 Ets1 下调。因此，这两条途径不是关键的 IKK 靶标，暗示其他尚未定义的 IKK 靶标在这个过程中发挥作用。
