title: 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 HMGB1(K282930R), 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.
authors.affiliation: From the Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Hwang
authors.affiliation: From the Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: Hyuk Soo
authors.initials: HS
authors.lastname: Choi
authors.affiliation: From the Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Ham
authors.affiliation: From the Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: Taesik
authors.initials: T
authors.lastname: Yoo
authors.affiliation: From the Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: Won Jin
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: The Department of Nursing, Semyung University, Jechon, Korea.
authors.forename: Kyung Shin
authors.initials: KS
authors.lastname: Paek
authors.affiliation: From the Department of Animal Biotechnology, Konkuk University, Seoul, Korea.
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000378:metabolism*; D057809:HEK293 Cells; D018922:HL-60 Cells; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018805:Sepsis / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1