Activation of Poly(ADP)-ribose Polymerase (PARP-1) Induces Release of the Pro-inflammatory Mediator HMGB1 from the Nucleus

• Published in: The Journal of biological chemistry Vol. 282; no. 24; pp. 17845 - 17854
• Main Authors: Ditsworth, Dara, Zong, Wei-Xing, Thompson, Craig B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.06.2007; American Society for Biochemistry and Molecular Biology
• Subjects: Active Transport, Cell Nucleus - physiology; Amino Acid Sequence; Animals; Cell Death - physiology; Cell Line; Cell Nucleus - metabolism; DNA Damage; Enzyme Activation; HMGB1 Protein - metabolism; Mice; Mice, Knockout; Molecular Sequence Data; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M701465200

Necrotic cells release inflammatory mediators that activate cytokine production from innate immune cells. One mediator of this activation is high mobility group box 1 protein (HMGB1). HMGB1 is normally a chromatin-associated protein and is sequestered at condensed chromatin during apoptosis. How it is released from chromatin during necrotic cell death is not known. Here we show that after DNA-alkylating damage, the activation of poly(ADP)-ribose polymerase (PARP) regulates the translocation of HMGB1 from the nucleus to the cytosol. This displaced HMGB1 is subject to release if the cell then loses plasma membrane integrity as a result of necrosis. Both full-length HMGB1 and a truncated form of HMGB1 lacking the highly conserved glutamate-rich C-terminal tail can induce macrophage activation and tumor necrosis factor-α production. However, displacement of HMGB1 from the nucleus following PARP activation requires the presence of the glutamate-rich C-terminal tail. Although the C-terminal tail is not the sole substrate for PARP modification of HMGB1, it appears to be required to destabilize HMGB1 association with chromatin following PARP-dependent chromatin modifications. These data suggest that PARP-dependent nuclear-to-cytosolic translocation of HMGB1 serves to establish the ability of cells to release this potent inflammatory mediator upon subsequent necrotic death.