Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Rep. 2013 Nov 27;5(4):1022-35. doi: 10.1016/j.celrep.2013.10.022. Epub 2013 Nov 14.
BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff(-/-) animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.
BAFF 是一种可溶性因子，对于 B 细胞的成熟和存活是必需的。BAFF-R 通过 TRAF3/NIK/IKK1 轴调控的非经典 NF-κB 信号通路进行信号转导。我们发现，在早期 B 细胞发育过程中 IKK1 的缺失会导致 B 细胞成熟和 BAFF 依赖性存活的部分损伤，但成熟 B 细胞中 IKK1 的失活并不影响存活。我们进一步表明，BAFF-R 通过 CD19 利用磷酸肌醇 3-激酶（PI3K）促进存活，并且 CD19 和 IKK1 的共同失活会导致过渡阶段 B 细胞成熟的严重阻滞。PI3K 在 BAFF-R 功能中的作用一致，PTEN 的失活介导了 Baff(-/-)动物中 B 细胞成熟和功能的部分挽救。升高的 PI3K 信号也会规避 BAFF 依赖性存活，这在自发性 B 细胞淋巴瘤模型中得到了证实。这些发现表明，PI3K 和 IKK1 的联合活性以依赖于上下文的方式驱动外周 B 细胞分化和存活。
