Format

Send to

Choose Destination
Sci Signal. 2019 May 14;12(581). pii: eaau0615. doi: 10.1126/scisignal.aau0615.

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

Author information

1
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
2
Immunology Program, Benaroya Research Institute, Seattle, WA 98101, USA.
3
Department of Immunology, University of Washington, Seattle, WA 98109, USA.
4
Seattle Children's Research Institute, Seattle, WA 98101, USA.
5
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
6
Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
7
Immunology Program, Benaroya Research Institute, Seattle, WA 98101, USA. jhamerman@benaroyaresearch.org.

Abstract

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.

PMID:
31088976
PMCID:
PMC6604799
[Available on 2019-11-14]
DOI:
10.1126/scisignal.aau0615

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center