Editors' ChoiceInflammation

From Nucleus to Secretory Vesicle

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Science's STKE  21 Oct 2003:
Vol. 2003, Issue 205, pp. tw412-TW412
DOI: 10.1126/stke.2003.205.tw412

High mobility group protein 1 (HMGB1) is an abundant nuclear protein associated with chromatin that functions in regulating transcription. HMGB1 is also released from necrotic cells, which stimulates inflammatory responses. In some cells, such as monocytes and macrophages, HMGB1 is secreted in response to various stimulating ligands. Bonaldi et al. investigated the mechanism by which a nuclear protein can accumulate in secretory vesicles in monocytes and macrophages. Two-dimensional electrophoresis showed that HMGB1 migrated as multiple spots and that activated monocytes [exposed to lipopolysaccharide (LPS)] exhibited an acidic major spot that was not abundant in resting monocytes. HMGB1 is acetylated, and mass spectrometry analysis of HMGB1 from calf thymus indicated that the isoforms of HMGB1 were consistent with multiple acetylation events. Treatment of a monocyte cell line or isolated macrophages with either LPS or the histone deacetylase inhibitor trichostatin A led to redistribution of HMGB1 from the nucleus to secretory granules and vesicles. In vitro, recombinant HMGB1 was a substrate for the major histone acetyltransferases (HATs: PCAF, CBP, p300). LPS-stimulated monocytes also exhibited increased histone acetylation, which suggests that cellular activation shifts the balance of HDAC and HAT activities toward acetylation. Acetylation of transcription factors is known to alter localization, but unlike other cases where acetylation promotes nuclear accumulation, for HMGB1, acetylation promotes cytoplasmic redistribution.

T. Bonaldi, F. Talamo, P. Scaffidi, D. Ferrera, A. Porto, A. Bachi, A. Rubartelli, A. Agresti, M. E. Bianchi, Monocytic cells hyperacetylated chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551-5560 (2003). [Abstract] [Full Text]

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