Abstract
Inflammatory signal-mediated release of high-mobility group box 1 (HMGB1) is a damage-associated molecular pattern or alarmin. The inflammatory functions of HMGB1 have been extensively investigated; however, less is known about the mechanisms controlling HMGB1 release. We show that SIRT1, the human homolog of the Saccharomyces cerevisiae protein silent information regulator 2, which is involved in cellular senescence and possibly the response to inflammation, forms a stable complex with HMGB1 in murine macrophage RAW264.7 cells. SIRT1 directly interacted with HMGB1 via its N-terminal lysine residues (28–30), and thereby inhibited HMGB1 release to improve survival in an experimental model of sepsis. By contrast, inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor-α promoted HMGB1 release by provoking its dissociation from SIRT1 dependent on acetylation, thereby increasing the association between HMGB1 and chromosome region maintenance 1, leading to HMGB1 translocation. In vivo infection with wild-type SIRT1 and HMGB1K282930R, a hypo-acetylation mutant, improved survival (85.7%) during endotoxemia more than infection with wild-type SIRT1 and HMGB1-expressing adenovirus, indicating that the acetylation-dependent interaction between HMGB1 and SIRT1 is critical for LPS-induced lethality. Taken together, we propose that SIRT1 forms an anti-inflammatory complex with HMGB1, allowing cells to bypass the response to inflammation.
Highlights
Inflammatory signal-mediated release of high-mobility group box 1 (HMGB1) is a damage-associated molecular pattern or alarmin
To further investigate the detailed mechanism, we examined the interaction between High-mobility group box 1 (HMGB1) and SIRT1 by co-immunoprecipitation
Similar conclusions were reached using in vitro protein-binding assays in which HMGB1-containing cell lysates were incubated with bacterially produced GST-fused SIRT1 protein (Fig. 1C). Consistent with these results, confocal microscopy showed the co-localization of ectopically expressed red fluorescent protein (RFP)-tagged HMGB1 and green fluorescent protein (GFP)-tagged SIRT1, mainly in the nuclei of HEK293T cells (Fig. 1D)
Summary
Inflammatory signal-mediated release of high-mobility group box 1 (HMGB1) is a damage-associated molecular pattern or alarmin. The importance of extracellular HMGB1 signals in disease pathogenesis was established because HMGB1 antagonists and a neutralizing anti-HMGB1 antibody significantly reduce the severity of inflammatory conditions such as sepsis, arthritis, colitis, and ischemia reperfusion[4,8–10] These observations indicate the importance of a mechanistic understanding of HMGB1 release from activated immune cells and the regulatory signaling pathways that control these processes. HMGB1 translocates from the nucleus to the cytoplasm upon the activation of monocytes by inflammatory signals such as LPS or tumor necrosis factor (TNF)-α through the hyper-acetylation of two major clusters of lysine residues within two nuclear localization sequence (NLS) sites[12]. This acetylation-associated translocation is mediated by chromosome region maintenance 1 (CRM1), a nuclear exportin[13]. Knockout or knockdown of SIRT1 leads to increased cytokine release, whereas SIRT1 activators inhibit production of TNF-α , monocyte chemoattractant protein 1, and interleukin (IL)-821,22, stressing the pivotal role of SIRT1 in cellular inflammatory control and the inflammatory response
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