期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 282, 期 24, 页码 17845-17854出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M701465200
关键词
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资金
- NCI NIH HHS [K01 CA098092-01A2, K01 CA098092-05, K01 CA098092-04, K01 CA098092-02, K01 CA098092-03, K01 CA098092, K01 CA098092-06] Funding Source: Medline
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-alpha 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.
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