Research ArticleImmunology

A Physical Interaction Between the Adaptor Proteins DOK3 and DAP12 Is Required to Inhibit Lipopolysaccharide Signaling in Macrophages

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Science Signaling  20 Aug 2013:
Vol. 6, Issue 289, pp. ra72
DOI: 10.1126/scisignal.2003801

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Adapting to Low-Dose LPS

The bacterial product lipopolysaccharide (LPS) is found in trace amounts in the circulation of patients with various chronic inflammatory conditions, including obesity, diabetes, and alcoholic liver disease. Such low doses of LPS stimulate the production of proinflammatory cytokines independently of nuclear factor κB, which is activated by higher LPS concentrations. Thus, understanding the mechanism of low-dose LPS signaling may help in the development of therapies to prevent excessive inflammation. Noting that the adaptor protein DAP12 inhibits LPS signaling, Peng et al. found that another adaptor, DOK3, was phosphorylated and recruited to DAP12 in response to LPS, leading to inhibition of extracellular signal–regulated kinase signaling and the decreased production of proinflammatory cytokines. Unlike wild-type mice, DOK3-deficient mice did not survive a sublethal dose of LPS. Furthermore, these mice had increased serum concentrations of proinflammatory cytokines. Together, these findings suggest the mechanism by which adaptor molecules converge to limit inflammatory signaling by LPS.

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