Program in Biotechnology, Columbia University, New York, NY 10032, USA.
J Immunol. 2011 Jul 15;187(2):619-25. doi: 10.4049/jimmunol.0903425. Epub 2011 Jun 17.
Macrophages are innate immune cells that play key roles in regulation of the immune response and in tissue injury and repair. In response to specific innate immune stimuli, macrophages may exhibit signs of endoplasmic reticulum (ER) stress and progress to apoptosis. Factors that regulate macrophage survival under these conditions are poorly understood. In this study, we identified B cell adapter protein (BCAP), a p85 PI3K-binding adapter protein, in promoting survival in response to the combined challenge of LPS and ER stress. BCAP was unique among nine PI3K adapter proteins in being induced >10-fold in response to LPS. LPS-stimulated macrophages incubated with thapsigargin, a sarcoplasmic/endoplasmic reticulum calcium ATPase inhibitor that induces ER stress, underwent caspase-3 activation and apoptosis. Macrophages from BCAP(-/-) mice exhibited increased apoptosis in response to these stimuli. BCAP-deficient macrophages demonstrated decreased activation of Akt, but not ERK, and, unlike BCAP-deficient B cells, expressed normal amounts of the NF-κB subunits, c-Rel and RelA. Retroviral transduction of BCAP-deficient macrophages with wild-type BCAP, but not a Y4F BCAP mutant defective in binding the SH2 domain of p85 PI3K, reversed the proapoptotic phenotype observed in BCAP-deficient macrophages. We conclude that BCAP is a nonredundant PI3K adapter protein in macrophages that is required for maximal cell survival in response to ER stress. We suggest that as macrophages engage their pathogenic targets, innate immune receptors trigger increased expression of BCAP, which endows them with the capacity to withstand further challenges from ongoing cellular insults, such as ER stress.
巨噬细胞是先天免疫细胞，在调节免疫反应和组织损伤及修复中发挥关键作用。在受到特定的先天免疫刺激时，巨噬细胞可能会表现出内质网（ER）应激的迹象，并进展为细胞凋亡。在这些条件下调节巨噬细胞存活的因素知之甚少。在这项研究中，我们发现 B 细胞衔接蛋白（BCAP），一种 p85 PI3K 结合衔接蛋白，在应对 LPS 和 ER 应激的联合挑战时促进存活。在对 LPS 的反应中，BCAP 在九种 PI3K 衔接蛋白中被诱导超过 10 倍，这使其具有独特性。用肌浆/内质网钙 ATP 酶抑制剂 thapsigargin（诱导 ER 应激）孵育 LPS 刺激的巨噬细胞会引发 caspase-3 激活和细胞凋亡。来自 BCAP(-/-) 小鼠的巨噬细胞对这些刺激的反应表现出更高的凋亡。BCAP 缺陷型巨噬细胞表现出 Akt 激活减少，但 ERK 激活没有减少，与 BCAP 缺陷型 B 细胞不同，它们表达正常数量的 NF-κB 亚基 c-Rel 和 RelA。用野生型 BCAP 而非不能结合 p85 PI3K SH2 结构域的 Y4F BCAP 突变体逆转了在 BCAP 缺陷型巨噬细胞中观察到的促凋亡表型。我们得出结论，BCAP 是巨噬细胞中一种非冗余的 PI3K 衔接蛋白，对于 ER 应激时的最大细胞存活是必需的。我们认为，当巨噬细胞与它们的致病靶标相互作用时，先天免疫受体会触发 BCAP 的表达增加，从而赋予它们承受来自持续细胞损伤（如 ER 应激）的进一步挑战的能力。
