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1.
Proc Natl Acad Sci U S A ; 109(1): 273-8, 2012 Jan 03.
Article in English | MEDLINE | ID: mdl-22187460

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-ß (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.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , B-Lymphocytes/enzymology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Toll-Like Receptors/metabolism , Adaptor Proteins, Signal Transducing/chemistry , Amino Acid Sequence , Animals , Enzyme Activation , HEK293 Cells , Humans , Inflammation/metabolism , Inflammation/pathology , Macrophages/metabolism , Macrophages/pathology , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Myeloid Differentiation Factor 88/metabolism , Protein Structure, Tertiary
2.
J Neurosci Res ; 88(15): 3399-413, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20882568

ABSTRACT

Intracellular aggregation of tau is a pathological hallmark in Alzheimer's disease and other tauopathies. The mechanisms underlying tau aggregation and the role that these aggregates play in neuronal death have remained controversial. To study these issues, we established a cell culture model of tauopathy using a hexameric peptide with the sequence (306)VQIVYK(311) located within the third microtubule-binding repeat of tau, rendered cell-permeable by a tag of nine arginine residues (R(9)). This peptide (VQIVYK-R(9)), designated as T-peptide, self-assembles in vitro into paired helical filament-like aggregates. Primary neuronal cells treated with T-peptide die within 24 hr. Neurodegeneration correlates with the ability of the peptide to aggregate. Two peptides with mutations in the hexameric core, K-peptide (VQIVKK) and VV-peptide (VQVVVK), that are incapable of aggregating are not toxic, whereas two other mutant peptides, V-peptide (VQVVYK) and F-peptide (VQIVFK), which aggregate, are also neurotoxic. Two other peptides that aggregate in vitro, but are not derived from tau, are not neurotoxic suggesting sequence dependence. Although localizing to the nucleus, T-peptide induces aggregation of cellular proteins in the cytoplasm. These aggregates are not caused by disruption of endogenous tau localization, although endogenous tau is reduced in neurons exposed to T-peptide. Interestingly, nonneuronal cells are less sensitive to T-peptide toxicity, recapitulating in part the selective loss of neurons in tauopathies. Moreover, T-peptide treatment leads to mitochondrial dysfunction, a common feature of neurodegenerative disorders. The model system described here represents a convenient paradigm for studying the mechanisms underlying tau aggregation and neurotoxicity and for identifying compounds that can prevent these effects.


Subject(s)
Neurons/metabolism , Neurons/pathology , Tauopathies/metabolism , Tauopathies/pathology , tau Proteins/metabolism , Animals , Blotting, Western , HEK293 Cells , Humans , Immunohistochemistry , Membrane Potential, Mitochondrial/physiology , Mutation , Nerve Degeneration/metabolism , Nerve Degeneration/pathology , Peptides , Rats , tau Proteins/chemistry , tau Proteins/genetics
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