The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1
The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1
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DOI：
10.1126/scisignal.aau0615
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发表时间：
2019-05-14
影响因子：
7.3
通讯作者：
Hamerman, Jessica A.
中科院分区：
文献类型：
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作者：
Carpentier, Samuel J.;Ni, Minjian;Hamerman, Jessica A.
磷酸肌醇3-激酶（PI 3 K）的B细胞衔接子（BCAP）是激活B细胞中的B细胞受体信号传导和巨噬细胞中的Toll样受体（TLR）信号传导下游的PI 3 K途径的信号传导衔接子。BCAP与I类PI 3 K的调节性p85亚基结合，是一种大的多结构域蛋白。我们使用蛋白质组学分析来鉴定巨噬细胞中的其他BCAP相互作用蛋白，并发现BCAP与caspase-1假底物抑制剂Flightless-1及其结合伴侣富含亮氨酸重复的Flightless相互作用蛋白2特异性相关。由于这些蛋白抑制NLRP 3炎性体，我们研究了BCAP在炎性体功能中的作用。BCAP抑制NLRP 3和NLRC 4诱导的半胱天冬酶-1活化、细胞死亡和巨噬细胞释放IL-1 β，与其对TLR引发的作用无关。因此，在BCAP缺陷小鼠中，假结核耶尔森氏菌突变体的caspase-1依赖性清除增强。从机制上讲，BCAP通过与Flightless-1的结合延迟了NLRP 3/ASC炎症前体中caspase-1原的募集和激活。因此，BCAP是一种多功能的信号适配器，抑制巨噬细胞中的关键病原体传感途径。
B cell adaptor for phosphoinositide 3-kinase (PI3K) (BCAP) is a signaling adaptor that activates the PI3K pathway downstream of B cell receptor signaling in B cells and Toll-like receptor (TLR) signaling in macrophages. BCAP binds to the regulatory p85 subunit of class I PI3K and is a large, multidomain protein. We used proteomic analysis to identify other BCAP-interacting proteins in macrophages and found that BCAP specifically associated with the caspase-1 pseudosubstrate inhibitor Flightless-1 and its binding partner leucine-rich repeat flightless-interacting protein 2. Because these proteins inhibit the NLRP3 inflammasome, we investigated the role of BCAP in inflammasome function. Independent of its effects on TLR priming, BCAP inhibited NLRP3- and NLRC4-induced caspase-1 activation, cell death, and IL-1 beta release from macrophages. Accordingly, caspase-1-dependent clearance of a Yersinia pseudotuberculosis mutant was enhanced in BCAP-deficient mice. Mechanistically, BCAP delayed the recruitment and activation of pro-caspase-1 within the NLRP3/ASC preinflammasome through its association with Flightless-1. Thus, BCAP is a multifunctional signaling adaptor that inhibits key pathogen-sensing pathways in macrophages.