A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress
A Requirement for the p85 PI3K Adapter Protein BCAP in the Protection of Macrophages from Apoptosis Induced by Endoplasmic Reticulum Stress
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DOI：
10.4049/jimmunol.0903425
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发表时间：
2011-07-15
影响因子：
4.4
通讯作者：
Greenberg, Steven
中科院分区：
文献类型：
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作者：
Song, SungWon;Chew, Claude;Greenberg, Steven
巨噬细胞是先天免疫细胞，在调节免疫反应和组织损伤和修复中发挥关键作用。在特定的先天免疫刺激下，巨噬细胞可能表现出内质网应激和细胞凋亡的迹象。在这些条件下调节巨噬细胞存活的因素尚不清楚。在这项研究中，我们发现B细胞适配蛋白（BCAP），一种p85 pi3k结合的适配蛋白，在LPS和内质网应激联合挑战下促进存活。在9个PI3K适配蛋白中，BCAP是唯一一个在LPS作用下被诱导10倍的蛋白。lps刺激的巨噬细胞用thapsigargin（一种肌浆/内质网钙atp酶抑制剂，可诱导内质网应激）孵育后，发生caspase-3活化和凋亡。BCAP（-/-）小鼠巨噬细胞在这些刺激下表现出增加的凋亡。与bcap缺陷的B细胞不同，巨噬细胞表现出Akt活性降低，但ERK活性不降低，并且与bcap缺陷的B细胞不同，nf - κ B亚基c-Rel和RelA表达量正常。逆转录病毒转导野生型BCAP缺陷巨噬细胞，而不是结合p85 PI3K的SH2结构域缺陷的Y4F BCAP突变体，逆转了在BCAP缺陷巨噬细胞中观察到的促凋亡表型。我们得出结论，在巨噬细胞中，BCAP是一种非冗余的PI3K适配蛋白，是响应内质网应激的最大细胞存活所必需的。我们认为，当巨噬细胞与致病靶点接触时，先天免疫受体会触发BCAP的表达增加，这使巨噬细胞具有抵御持续细胞损伤（如内质网应激）的能力。免疫学杂志，2011,18(7):619-625。
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-kappa B 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. The Journal of Immunology, 2011, 187: 619-625.