title: Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt.
abstract: Toll like receptors (TLRs) use Toll-IL-1 receptor (TIR) domain-containing adapters, such as myeloid differentiation primary response gene 88 (MyD88) and TIR domain-containing adapter inducing IFN-β (TRIF), to induce activation of transcription factors, including NF-κB, MAP kinases, and IFN regulatory factors. TLR signaling also leads to activation of PI3K, but the molecular mechanism is not understood. Here we have discovered a unique role for B-cell adapter for PI3K (BCAP) in the TLR-signaling pathway. We find that BCAP has a functional N-terminal TIR homology domain and links TLR signaling to activation of PI3K. In addition, BCAP negatively regulates proinflammatory cytokine secretion upon TLR stimulation. In vivo, the absence of BCAP leads to exaggerated recruitment of inflammatory myeloid cells following infections and enhanced susceptibility to dextran sulfate sodium-induced colitis. Our results demonstrate that BCAP is a unique TIR domain-containing TLR signaling adapter crucial for linking TLRs to PI3K activation and regulating the inflammatory response.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ty Dale
authors.initials: TD
authors.lastname: Troutman
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fulenchek
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Bazan
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Pasare
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; C487978:Pik3ap1 protein, mouse; D051193:Toll-Like Receptors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt