Research ArticleInflammasomes

The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1

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Science Signaling  14 May 2019:
Vol. 12, Issue 581, eaau0615
DOI: 10.1126/scisignal.aau0615

BCAPing inflammasome activation

The PI3K adaptor protein BCAP limits cellular responses to TLR stimulation and IL-1β. Using proteomics analysis, Carpentier et al. showed that BCAP interacted with Flightless-1 and its binding partner leucine-rich repeat Flightless-1–interacting protein 2 (LRRFIP2), which promoted an association between BCAP and the inflammasome component NLRP3. In macrophages, BCAP reduced the abundance of active caspase-1, maturation of the cytokine IL-1β, and cell death after exposure to the toxin nigericin or bacterial infection. Kinetic analyses determined that BCAP delayed recruitment of pro–caspase-1 to intracellular inflammasome foci and loss of BCAP promoted bacterial clearance in mice. These data identify a distinct role for this PI3K adaptor in preventing excessive, potentially harmful activation of NLRP3 and NLRC4 inflammasomes.


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-1β 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.

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