Negative Regulation of TLR Signaling by BCAP Requires Dimerization of Its DBB Domain

Abstract

The B cell adaptor protein (BCAP) is a multimodular regulator of inflammatory signaling in diverse immune system cells. BCAP couples TLR signaling to phosphoinositide metabolism and inhibits MyD88-directed signal transduction. BCAP is recruited to the TLR signalosome forming multitypic interactions with the MAL and MyD88 signaling adaptors. In this study, we show that indirect dimerization of BCAP TIR is required for negative regulation of TLR signaling. This regulation is mediated by a transcription factor Ig (TIG/IPT) domain, a fold found in the NF-kB family of transcription factors. We have solved the crystal structure of the BCAP TIG and find that it is most similar to that of early B cell factor 1 (EBF1). In both cases, the dimer is stabilized by a helixloop-helix motif at the C terminus and interactions between the b-sheets of the Ig domains. BCAP is exclusively localized in the cytosol and is unable to bind DNA. Thus, the TIG domain is a promiscuous dimerization module that has been appropriated for a range of regulatory functions in gene expression and signal transduction.

Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons

“…By focusing on the two pathways involved in cGAMP and LPS signaling, the only gene with significantly altered expression in D2I fibroblast was PIK3AP1 , coding BCAP, an adaptor protein coupling various receptors, like B cell receptor and Toll-like receptors, to PI3K [ 35 ]. BCAP is a major modulator of TLR signaling, downregulating NF-kB activation [ 36 ] and favoring type I IFN induction [ 21 ]. Very recent data showed that activation of the STING-Lyn pathway leads to PIK3AP1 hyper-expression, which can be relevant to the development of SLE in lupus prone mice, thus adding substance to our findings [ 37 ].…”

TIRAP in the Mechanism of Inflammation

“…BCAP is a dimeric protein and its oligomerization depends on its ANK (ankyrin repeat) and DBB (Dof/BANK1/BCAP) domains. A recently concluded study clearly defines the importance of DBB domain in dimerization and its role in TIRAP-BCAP interaction ( 39 ). The monomeric BCAP, though fails to negatively regulate the TLR signaling suggesting that only domain dimerization drives the negative response.…”

“…Such a filament could be disrupted by dimeric, and not monomeric, BCAP. Another angle suggest BCAP phosphoinositide metabolism, which cleaves PIP2 to DAG and IP3 and hence deprives TIRAP for its membrane anchor required for TLR signaling ( 39 ). Overall, the BCAP association mainly with TIRAP and p85α provides novel directions for regulatory pathways in inflammation.…”

Re-identification and characterization of grass carp Ctenopharyngodon idella TLR20

“…When MAMPs bind to the ECD, the TIR domain of each TLR recruits its respective adapters. In mammals, there are a total of seven adapters involved, namely MyD88, MAL, TRIF, TRAM, SARM, BCAP, and SCIMP [ 22 , 27 , 32 , 36 ]. These adaptors then deliver signals downstream to activate either the NF-κB signaling pathway or the IFN signaling pathway [ 16 , 35 , 57 ].…”