title: Poly(ADP-ribose) polymerase 1-sirtuin 1 functional interplay regulates LPS-mediated high mobility group box 1 secretion.
abstract: Pathophysiological conditions that lead to the release of the prototypic damage-associated molecular pattern molecule high mobility group box 1 (HMGB1) also result in activation of poly(ADP-ribose) polymerase 1 (PARP1; now known as ADP-ribosyl transferase 1 [ARTD1]). Persistent activation of PARP1 promotes energy failure and cell death. The role of poly(ADP-ribosyl)ation in HMGB1 release has been explored previously; however, PARP1 is a versatile enzyme and performs several other functions including cross-talk with another nicotinamide adenine dinucleotide- (NAD(+)) dependent member of the Class III histone deacetylases (HDACs), sirtuin-1 (SIRT1). Previously, it has been shown that the hyperacetylation of HMGB1 is a seminal event prior to its secretion, a process that also is dependent on HDACs. Therefore, in this study, we seek to determine if PARP1 inhibition alters LPS-mediated HMGB1 hyperacetylation and subsequent secretion due to its effect on SIRT1. We demonstrate in an in vitro model that LPS treatment leads to hyperacetylated HMGB1 with concomitant reduction in nuclear HDAC activity. Treatment with PARP1 inhibitors mitigates the LPS-mediated reduction in nuclear HDAC activity and decreases HMGB1 acetylation. By utilizing an NAD(+)-based mechanism, PARP1 inhibition increases the activity of SIRT1. Consequently, there is an increased nuclear retention and decreased extracellular secretion of HMGB1. We also demonstrate that PARP1 physically interacts with SIRT1. Further confirmation of this data was obtained in a murine model of sepsis, that is, administration of PJ-34, a specific PARP1 inhibitor, led to decreased serum HMGB1 concentrations in mice subjected to cecal ligation and puncture (CLP) as compared with untreated mice. In conclusion, our study provides new insights in understanding the molecular mechanisms of HMGB1 secretion in sepsis.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Walko
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Caro
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jon
authors.initials: J
authors.lastname: Piganelli
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Departments of Critical Care Medicine and Pediatrics, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.affiliation: Departments of Critical Care Medicine and Pediatrics, University of Pittsburgh School of Medicine and Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Aneja
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008070:Lipopolysaccharides; D008264:Macrophages; D008822:Mice, Transgenic; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; D007546:Isoquinolines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C095653:1,5-dihydroxyisoquinoline; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D056564:Sirtuin 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1