HMGB1 review: Localization and synthesis

hmgb1 activation

High mobility group box-1 protein (HMGB1, NP_002119) is a non-histone chromosome binding protein found in eukaryotic nuclei 35 years ago because of its performance on polyacrylamide gel electrophoresis. HMGB1 is a single chain polypeptide containing 215 amino acid residues which is highly conserved. HMGB1 has rich positively charged lysine at N-terminal and negatively charged aspartic acid and glutamic acid at C-terminal (acidic tail). HMGB1 molecular weight of about 24894 Da. HMGB1 has an A box includes 9-79 amino acid residue and B box includes the 95-163 amino acid residue. Its receptor binding domain containing only the glutamic acid and aspartic acid residues body. Functional analysis of the structure shows that the B box of HMGB1 is the functional region where is involved in inflammation. Also the A box is the antagonistic site of the B box. Both A box and B box can bind to DNA and participate in the folding and twisting of DNA double strands.

As a nucleoprotein, HMGB1 is commonly found in mammalian tissue cells, but is highly expressed in thymus, lymphoid tissue, testis and neonatal liver. Previously, people were concerned about the function of HMGB1 as a nuclear protein until 1999. HMGB1 was reported as a potential pro-inflammatory cytokine involved in the pathogenesis of sepsis. People take HMGB1 as an inflammatory factor which has important significance.

HMGB1 localization and synthesis

HMGB1 is mainly present in the nucleus when the cells are in steady state. When there is extracellular stimulus, HMGB1 lysine residues are acetylated and then released to the extracellular. HMGB1 is different from other secretory proteins, because HMGB1 lacks the signal peptide, so it is not transported through the endoplasmic reticulum nor Golgi body. Lysophospholipids (Lysophosphatidylcholine) triggers the release of nuclear HMGB1 into the cells. Youn et al found that TNFalpha stimulates macrophages, the release of HMGB1 depends on its phosphorylation. It is not clear about the specific mechanisms of these two different types of secretion.

There are three possible sources of extracellular HMGB1:

  • When macrophages, monocytes, pituitary cells, epithelial cells are stimulated by LPS, TNFalpha, IFNgamma or IL-1, HMGB1 can be actively secreted into the cells which leads to¬†inflammation;
  • Cell damage or necrosis can release HMGB1, but the process of apoptosis does not release HMGB1;
  • Some of their own tissue cells in the external environment changes through Non-classical way to automatically secrete HMGB1, acting on its own or surrounding tissue, to induce cell migration, differentiation and regeneration. Wang et al stimulate the macrophages with LPS and TNF and detect the level of intracellular HMGB1 mRNA. HMGB1 mRNA levels were not upregulated after stimulation. Immunofluorescence staining shows HMGB1 was significantly transferred from the nucleus to the cytoplasm, suggesting that HMGB1 secreted by macrophages was not newly synthesized but transferred from nucleus. However, it is worth noting that there is molecular difference between macrophages actively secreted HMGB1 and necrotic cells passively released HMGB1. The mechanism is unclear.

Also published on Medium.

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