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MARCKS as a Negative Regulator of Lipopolysaccharide Signaling

Mancek-Keber, M., Bencina, M., Japelj, B., Panter, G., Andra, J., Brandenburg, K., Triantafilou, Martha ORCID:, Triantafilou, Kathy ORCID: and Jerala, R. 2012. MARCKS as a Negative Regulator of Lipopolysaccharide Signaling. The Journal of Immunology 188 (8) , pp. 3893-3902. 10.4049/jimmunol.1003605

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Myristoylated alanine-rich C kinase substrate (MARCKS) is an intrinsically unfolded protein with a conserved cationic effector domain, which mediates the cross-talk between several signal transduction pathways. Transcription of MARCKS is increased by stimulation with bacterial LPS. We determined that MARCKS and MARCKS-related protein specifically bind to LPS and that the addition of the MARCKS effector peptide inhibited LPS-induced production of TNF-α in mononuclear cells. The LPS binding site within the effector domain of MARCKS was narrowed down to a heptapeptide that binds to LPS in an extended conformation as determined by nuclear magnetic resonance spectroscopy. After LPS stimulation, MARCKS moved from the plasma membrane to FYVE-positive endosomes, where it colocalized with LPS. MARCKS-deficient mouse embryonic fibroblasts (MEFs) responded to LPS with increased IL-6 production compared with the matched wild-type MEFs. Similarly, small interfering RNA knockdown of MARCKS also increased LPS signaling, whereas overexpression of MARCKS inhibited LPS signaling. TLR4 signaling was enhanced by the ablation of MARCKS, which had no effect on stimulation by TLR2, TLR3, and TLR5 agonists. These findings demonstrate that MARCKS contributes to the negative regulation of the cellular response to LPS.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Publisher: American Association of Immunologists
ISSN: 0022-1767
Last Modified: 21 Oct 2022 09:41

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