Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion

High Mobility Group 1 protein (HMGB1) is a chromatin component that, when leaked out by necrotic cells, triggers inflammation. HMGB1 can also be secreted by activated monocytes and macrophages, and functions as a late mediator of inflammation. Secretion of a nuclear protein requires a tightly controlled relocation program. We show here that in all cells HMGB1 shuttles actively between the nucleus and cytoplasm. Monocytes and macrophages acetylate HMGB1 extensively upon activation with lipopolysaccharide; moreover, forced hyperacetylation of HMGB1 in resting macrophages causes its relocalization to the cytosol. Cytosolic HMGB1 is then concentrated by default into secretory lysosomes, and secreted when monocytic cells receive an appropriate second signal.

[1]  A. Kretsovali,et al.  Acetylation by PCAF Enhances CIITA Nuclear Accumulation and Transactivation of Major Histocompatibility Complex Class II Genes , 2000, Molecular and Cellular Biology.

[2]  A. Shevchenko,et al.  Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. , 1996, Analytical chemistry.

[3]  A. Travers,et al.  HMG1 and 2, and related 'architectural' DNA-binding proteins. , 2001, Trends in biochemical sciences.

[4]  S. Müller,et al.  The double life of HMGB1 chromatin protein: architectural factor and extracellular signal , 2001 .

[5]  T. Misteli,et al.  Release of chromatin protein HMGB1 by necrotic cells triggers inflammation , 2002, Nature.

[6]  Michael Bustin,et al.  Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. , 2003, Blood.

[7]  M. Bianchi,et al.  HMGB proteins and gene expression. , 2003, Current opinion in genetics & development.

[8]  M. Yamakuchi,et al.  High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. , 2003, Arthritis and rheumatism.

[9]  G. Längst,et al.  High Mobility Group 1 Protein Is Not Stably Associated with the Chromosomes of Somatic Cells , 1997, The Journal of cell biology.

[10]  K. Tracey,et al.  High Mobility Group 1 Protein (Hmg-1) Stimulates Proinflammatory Cytokine Synthesis in Human Monocytes , 2000, The Journal of experimental medicine.

[11]  Emma J. Blott,et al.  Secretory lysosomes , 2002, Nature Reviews Molecular Cell Biology.

[12]  Michael Bustin,et al.  Regulation of DNA-Dependent Activities by the Functional Motifs of the High-Mobility-Group Chromosomal Proteins , 1999, Molecular and Cellular Biology.

[13]  K. Tracey,et al.  HMG-1 as a late mediator of endotoxin lethality in mice. , 1999, Science.

[14]  I. Talianidis,et al.  Acetylation regulates transcription factor activity at multiple levels. , 2000, Molecular cell.

[15]  U. Andersson,et al.  High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis. , 2003, Arthritis and rheumatism.

[16]  P. Yaciuk,et al.  Acetylation of the Adenovirus-transforming Protein E1A Determines Nuclear Localization by Disrupting Association with Importin-α* , 2002, The Journal of Biological Chemistry.

[17]  V. Allfrey,et al.  Studies of acetylation and deacetylation in high mobility group proteins. Identification of the sites of acetylation in HMG-1. , 1979, The Journal of biological chemistry.

[18]  M. Bustin,et al.  Antibodies against chromosomal HMG proteins stain the cytoplasm of mammalian cells , 1979, Cell.

[19]  A. Aguzzi,et al.  The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice , 1999, Nature Genetics.

[20]  G. Längst,et al.  The DNA chaperone HMGB1 facilitates ACF/CHRAC‐dependent nucleosome sliding , 2002, The EMBO journal.

[21]  S. Knapp,et al.  Thermodynamics of HMGB1 interaction with duplex DNA. , 2001, Biochemistry.

[22]  S. Müller,et al.  The High Mobility Group (Hmg) Boxes of the Nuclear Protein Hmg1 Induce Chemotaxis and Cytoskeleton Reorganization in Rat Smooth Muscle Cells , 2001, The Journal of cell biology.

[23]  M. Torrisi,et al.  The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles. , 1999, Molecular biology of the cell.

[24]  V. Allfrey,et al.  Studies of acetylation and deacetylation in high mobility group proteins. Identification of the sites of acetylation in high mobility group proteins 14 and 17. , 1981, The Journal of biological chemistry.

[25]  M. Bianchi,et al.  The nuclear protein HMGB1 is secreted by monocytes via a non‐classical, vesicle‐mediated secretory pathway , 2002, EMBO reports.

[26]  D. L. Weeks,et al.  RanGTP-Regulated Interactions of CRM1 with Nucleoporins and a Shuttling DEAD-Box Helicase , 1999, Molecular and Cellular Biology.

[27]  C. Bovolenta,et al.  A selective defect of IFN-gamma- but not of IFN-alpha-induced JAK/STAT pathway in a subset of U937 clones prevents the antiretroviral effect of IFN-gamma against HIV-1. , 1999, Journal of immunology.

[28]  K. Yoshida,et al.  Nuclear accumulation of HMG2 protein is mediated by basic regions interspaced with a long DNA-binding sequence, and retention within the nucleus requires the acidic carboxyl terminus. , 1997, Biochemistry.

[29]  B. Rost,et al.  Finding nuclear localization signals , 2000, EMBO reports.

[30]  A. Poggi,et al.  Control of interleukin‐18 secretion by dendritic cells: role of calcium influxes , 2000, FEBS letters.

[31]  K. Tracey,et al.  HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. , 2002, Gastroenterology.