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LPS-induced clustering of CD14 triggers generation of PI(4,5)P2.*

Posted by on in 2015
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  • Płóciennikowska A1Zdioruk MI1Traczyk G1Świątkowska A1Kwiatkowska K2. 2015. J Cell Sci. 128(22):4096-111. doi: 10.1242/jcs.173104. Epub 2015 Oct 7.
    • 1Nencki Institute of Experimental Biology, Laboratory of Molecular Membrane Biology, 3 Pasteur St., Warsaw 02-093, Poland.
    • 2Nencki Institute of Experimental Biology, Laboratory of Molecular Membrane Biology, 3 Pasteur St., Warsaw 02-093, Poland k.kwiatkowska@nencki.gov.pl.

    Abstract

    Bacterial lipopolysaccharide (LPS) induces strong pro-inflammatory reactions after sequential binding to CD14 protein and TLR4 receptor. Here, we show that CD14 controls generation of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] in response to LPS binding. In J774 cells and HEK293 cells expressing CD14 exposed to 10-100 ng/ml LPS, the level of PI(4,5)P2 rose in a biphasic manner with peaks at 5-10 min and 60 min. After 5-10 min of LPS stimulation, CD14 underwent prominent clustering in the plasma membrane, accompanied by accumulation of PI(4,5)P2 and type-I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) isoforms Iα and Iγ (encoded by Pip5k1a and Pip5k1c, respectively) in the CD14 region. Clustering of CD14 with antibodies, without LPS and TLR4 participation, was sufficient to trigger PI(4,5)P2 elevation. The newly generated PI(4,5)P2 accumulated in rafts, which also accommodated CD14 and a large portion of PIP5K Iα and PIP5K Iγ. Silencing of PIP5K Iα and PIP5K Iγ, or application of drugs interfering with PI(4,5)P2 synthesis and availability, abolished the LPS-induced PI(4,5)P2 elevation and inhibited downstream pro-inflammatory reactions. Taken together, these data indicate that LPS induces clustering of CD14, which triggers PI(4,5)P2 generation in rafts that is required for maximal pro-inflammatory signaling of TLR4.

    © 2015. Published by The Company of Biologists Ltd.

    KEYWORDS:

    CD14; Lipopolysaccharide; Phosphatidylinositol4,5-bisphosphate; TLR4

    PMID:
     
    26446256
     
    [PubMed - in process]
    *The HRP Chicken anti-Glutathione S Transferase (GST) used in this publication was supplied by Gallus Immunotech.

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