B-cell adaptor for PI3K (BCAP) negatively regulates Toll-like receptor signaling through activation of PI3K

Abstract

Toll-like receptors (TLRs) recognize pathogens and their components, thereby initiating immune responses to infectious organisms. TLR ligation leads to the activation of NF-κB and MAPKs through well-defined pathways, but it has remained unclear how TLR signaling activates PI3K, which provides an inhibitory pathway limiting TLR responses. Here, we show that the signaling adapter B-cell adaptor for PI3K (BCAP) links TLR signaling to PI3K activation. BCAP-deficient macrophages and mice are hyperresponsive to TLR agonists and have reduced PI3K activation. The ability of BCAP to inhibit TLR responses requires its capacity to bind PI3K. BCAP is constitutively phosphorylated and associated with the p85 subunit of PI3K in macrophages. This tyrosine-phosphorylated BCAP is transiently enriched in the membrane fraction in response to LPS treatment, suggesting a model whereby TLR signaling causes the phosphorylation of the small amount of BCAP that is associated with membranes in the resting state or the translocation of phosphorylated BCAP from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated BCAP at the membrane with its associated PI3K would then allow for the catalysis of Ptd Ins P2 to Ptd Ins P3 and downstream PI3K-dependent signals. Therefore, BCAP is an essential activator of the PI3K pathway downstream of TLR signaling, providing a brake to limit potentially pathogenic excessive TLR responses.inflammatory response | innate immunity

Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

“…This hypothesis is further supported by the overlapping phenotype of BCAPdeficient and Lyn-deficient macrophages stimulated with TLR agonists. 21,68,94 However, this hypothesis remains to be experimentally tested.…”

“…Critically, as is the case for BCAP mediated PI3K activation through BCR stimulation, tyrosine phosphorylation of BCAP is required for optimal restriction of inflammatory cytokine production, suggesting the requirement of tyrosine phosphorylation of BCAP for TLR mediated PI3K activation. 94 At present, the tyrosine kinase mediating BCAP phosphorylation in TLR-stimulated cells remains unknown. Notably, the SRC family kinase Lyn is implicated in phosphorylation of BCAP in B cells stimulated through their receptor or CD19 crosslinking.…”

“…[91][92][93] In addition to B cells, BCAP is expressed by macrophages and NK cells, and acts as a negative regulator of inflammation through TLRs and NK cell receptors respectively. 21,[94][95][96] Indeed, BCAP is critical in mediating PI3K/Akt activation upon stimulation of cells with TLR ligands (Fig. 2).…”

“…2). 21,94,97 BCAP mechanistically connects TLRs to PI3K through a cryptic TIR domain at the N terminus of BCAP, which is utilized for recruitment to the TLR signaling apparatus (Fig. 1).…”

Signaling networks in Leishmania macrophages deciphered through integrated systems biology: a mathematical modeling approach

“…Recent studies have also shown that PI3 K is an endogenous suppressor of IL-12 production triggered by TLR signaling and limits excessive Th1 polarization. It is possible that crosstalk occurs between these three negative regulatory signaling pathways in TLR signaling (Troutman et al 2012;Ni et al 2012). Despite these strong immune responses, Leishmania persist in a latent form, which suggests a dynamic relationship between the host immune system and Leishmania that results in a balance between host survival and its control.…”