Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI.
Department of Laboratory Medicine, University of California, San Francisco School of Medicine, San Francisco, CA.
J Immunol. 2024 Jun 1;212(11):1639-1646. doi: 10.4049/jimmunol.2300784.
Recently, we reported that preexposure of B cells to IL-4 induced an alternate, signalosome-independent BCR signaling pathway leading to protein kinase C (PKC)δ phosphorylation (pTyr311), which occurs in the membrane compartment. This is considered to represent a form of receptor crosstalk and signal integration. Unlike the classical BCR signaling pathway, Lyn kinase is indispensable for BCR-induced downstream events in the alternate pathway. Our previous report that alternate BCR signaling leading to ERK phosphorylation is triggered by LPS and PAM3CSK4 (much like IL-4) raises the possibility that other signaling outcomes such as PKCδ phosphorylation might be similarly affected. To explore the range of mediators capable of producing an alternate pathway for BCR signaling, we examined PKCδ translocation and phosphorylation in LPS- and PAM3CSK4-treated B cells stimulated by anti-Ig. We found that LPS and PAM3CSK4 alter the signaling pathway used by the BCR to produce PKCδ phosphorylation. As with IL-4, elements of the signalosome are not needed for PKCδ phosphorylation when BCR triggering occurs after LPS and PAM3CSK4. However, with LPS and PAM3CSK4, anti-Ig-induced phosphorylation of PKCδ takes place in the cytosol, in contrast to the IL-4-induced alternate pathway, wherein PKCδ phosphorylation occurs in the membrane. Furthermore, the BCR signaling pathway induced by LPS and PAM3CSK4 differs from that induced by IL-4 by not requiring Lyn. Thus, an alternate, signalosome-independent BCR signaling pathway for PKCδ phosphorylation is induced by TLR agonists but differs in important ways from the alternate pathway induced by IL-4.
最近，我们报道称，B 细胞预先暴露于 IL-4 会诱导一种替代的、信号转导体非依赖性 BCR 信号通路，导致蛋白激酶 C（PKC）δ 磷酸化（pTyr311），该过程发生在膜区。这被认为代表了一种受体串扰和信号整合形式。与经典的 BCR 信号通路不同，Lyn 激酶对于替代途径中 BCR 诱导的下游事件是不可或缺的。我们之前的报告表明，导致 ERK 磷酸化的替代 BCR 信号是由 LPS 和 PAM3CSK4（与 IL-4 非常相似）触发的，这使得其他信号转导产物，如 PKCδ 磷酸化，也可能受到类似的影响。为了探索能够产生替代 BCR 信号通路的介质范围，我们研究了 LPS 和 PAM3CSK4 处理的 B 细胞在抗 Ig 刺激下的 PKCδ 易位和磷酸化。我们发现，LPS 和 PAM3CSK4 改变了 BCR 用于产生 PKCδ 磷酸化的信号通路。与 IL-4 一样，当 BCR 触发发生在 LPS 和 PAM3CSK4 之后时，信号转导体的元件对于 PKCδ 磷酸化不是必需的。然而，与 IL-4 诱导的替代途径不同，LPS 和 PAM3CSK4 诱导的抗 Ig 诱导的 PKCδ 磷酸化发生在细胞质中，而不是在膜中。此外，LPS 和 PAM3CSK4 诱导的 BCR 信号通路与 IL-4 诱导的信号通路不同，因为它不需要 Lyn。因此，TLR 激动剂诱导了一种替代的、信号转导体非依赖性的 PKCδ 磷酸化 BCR 信号通路，但与 IL-4 诱导的替代途径在重要方面存在差异。
