title: 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.
authors.affiliation: Immunology Program, Benaroya Research Institute, Seattle, WA 98101, USA.
authors.forename: Minjian
authors.initials: M
authors.lastname: Ni
authors.forename: Alexander W
authors.initials: AW
authors.lastname: MacFarlane
authors.forename: Michelle
authors.initials: M
authors.lastname: Toft
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hamerman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D000072377:Syk Kinase; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C000606205:Nfkbia protein, mouse; C487978:Pik3ap1 protein, mouse; D021122:Protein Subunits; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases