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- W1548381998 abstract "Abstract Innate immune activation via Toll-like receptors (TLRs), although critical for host defense against infection, must be regulated to prevent sustained cell activation that can lead to cell death. Cells previously stimulated with lipopolysaccharide (LPS) develop endotoxin tolerance making the cells hypo-responsive to additional TLR stimulation. We investigated the role of downstream of tyrosine kinase 3 (DOK3) in regulating TLR responses and endotoxin tolerance of macrophages and find that DOK3 is a negative regulator of TLR4 and TLR9. Mechanistically, LPS induces ubiquitin-mediated degradation of DOK3 and the Ras activator SOS1, in a DOK3-dependent manner, with subsequent inhibition of ERK activation and repression of IL-1β and IL-10 production. In LPS-induced tolerant macrophages, DOK3 expression remains stable allowing it to sequester SOS1 and Grb2 preventing ERK activation. DOK3-deficient cells demonstrate enhanced sensitivity to LPS and to LPS-induced tolerance becoming tolerant at lower levels of LPS than wild type cells. Additionally, DOK3 negatively regulates several mediators of tolerance including SHIP1, IRAK-M, and SOCS1. Taken together, the absence of DOK3 increases LPS signaling leading to more rapid induction of LPS-induced tolerance. Thus, DOK3 mediates LPS responses and the induction of endotoxin tolerance by a novel mechanism of SOS1 regulation." @default.
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- W1548381998 date "2012-05-01" @default.
- W1548381998 modified "2023-09-27" @default.
- W1548381998 title "Targeted degradation of DOK3 regulates LPS responses and endotoxin tolerance (180.13)" @default.
- W1548381998 doi "https://doi.org/10.4049/jimmunol.188.supp.180.13" @default.
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