Reactome: A Curated Pathway Database

HMGB1 binds LTP

Stable Identifier
Homo sapiens
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Lipoteichoic acid (LTA) is a component of the cell wall of Gram-positive bacteria. LTA induces a toll-like receptor 2 (TLR2)-mediated inflammatory response upon initial binding to coreceptors CD36 and CD14 (Nilsen NJ et al. 2008).

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that under normal conditions binds and bends DNA and facilitates gene transcription. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013). HMGB1 has been implicated in TLR2-mediated inflammation (Yu M et al. 2006; Park JS et al. 2006). Addition of HMGB1 induced cellular activation and TLR2- and TLR4-mediated NFkappaB-dependent transcription in TLR2- or TLR4-transfected human embryonic kidney-293 (HEK293) cells (Park JS et al. 2006). Mouse Tlr2 was found to associate with immunoprecipitated Hmgb1 from mouse macrophage-like RAW264.7 cell lysates (Park JS et al. 2006). Anti-TLR2 antibodies dose-dependently attenuated HMGB1-induced IL-8 release in TLR2-expressing HEK293 cells and markedly reduced HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells (Yu M et al. 2006). Moreover, results of ELISA, surface plasmon resonance and native PAGE electrophoretic mobility shift analyses indicated that HMGB1 binds LTA in a concentration-dependent manner and that this binding is inhibited by LBP (Kwak MS et al. 2015). Native PAGE, fluorescence-based transfer and confocal imaging analyses indicated that HMGB1 catalytically disaggregated LTA transfering LTA to CD14. NFkappaB p65 nuclear transmigration, degradation of IkBalpha and reporter assay results demonstrated that NFkappaB activity in HEK293-hTLR2/6 cells was significantly upregulated by a mixture of LTA and soluble CD14 in the presence of HMGB1 (Kwak MS et al. 2015). Furthermore, the production of TNFalpha and IL6 in murine J774A.1 and RAW264.7 cells increased significantly following treatment with a mixture of LTA and HMGB1 compared with treatment with LTA or HMGB1 alone (Kwak MS et al. 2015). Thus, HMGB1 was proposed to play an important role in LTA-mediated inflammation by binding to LTA and transferring LTA to CD14, which is subsequently transferred to TLR2:TLR6 to induce an inflammatory response.

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