Deacetylation-mediated interaction of SIRT1-HMGB1 improves survival in a mouse model of endotoxemia

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.

Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells

“…1C), although the majority of HMGB1 protein remained in the nuclear region (cytosol HMGB1; 19.5 ± 10.2 %, p < 0.05). These results were consistent with previous report [28], and suggested that HMGB1 released from nucleus is capable of inducing signal transduction. Moreover, using MAP2 to label neurons, and non-MAP2 positive stains to mark non-neuronal cells (i.e., astrocytes), HMGB1 translocation from the nucleus to the cytosol was comparable between neurons and astrocytes in the present mixed cell culture paradigm.…”

“…Because epilepsy, is a network disease, there is limited direct translational application of the present cell culture paradigm, which represents an artificial system with a specific number of neural subtypes. Nonetheless, the present results advance the concept of HMGB1 post-translational modifications [28, 55], in our understanding of disease pathology and developing treatments for epilepsy-related hyperexcitability.…”

“…Post-translational modification has been demonstrated to exert a pivotal role for the translocation of HMGB1 [6, 28-32], therefore, we sought to determine whether KA treatment in PRNCs triggered HMGB1 post-translational modification. Immunoprecipitation (IP) analysis demonstrated that HMGB1 was acetylated (Fig.…”

Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis

“…Furthermore, we discovered that NR pretreatment markedly reduced plasma HMGB1 levels in septic mice, which correlated with an attenuation of lung injury and myocardial dysfunction in septic mice. Studies have demonstrated that hyper-acetylation of HMGB1 promotes its nucleus-to-cytoplasm translocation and release in activated immune cells [37]. SIRT1 induces de-acetylation of HMGB1 and thus, inhibits its release.…”

SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model

“…Importantly, RSV was found to effectively inhibit inflammatory responses by acting as a SIRT1 activator [25]. Some studies have shown that HMGB1 is a main downstream deacetylated target of SIRT1 [26] and SIRT1 activation inhibited HMGB1 secretion [27]. In contrast, some reports have claimed that SIRT1 inhibition, but not activation, could be a novel way to treat sepsis in its hypoinflammatory phase [28].…”