HMGB1 protein and linker histone H1 have overlapping binding sites in the nucleosome. HMGB1 has been implicated in many DNA-dependent processes in chromatin involving binding of specific proteins, including transcription factors, to DNA sites pre-bent by HMGB1. HMGB1 can also act as an extracellular signaling molecule by promoting inflammation, tumor growth a metastasis. Many of the intra- and extracellular functions of HMGB1 depend on redox-sensitive cysteine residues of the protein. Here we report that mild oxidization of HMGB1 (and much less mutation of cysteines involved in disulphide bond formation) can severely compromise the functioning of the protein as a DNA chaperone by inhibiting its ability to unwind or bend DNA. Histone H1 (via the highly basic C-terminal domain) significantly inhibits DNA bending by the full-length HMGB1, and the inhibition is further enhanced upon oxidization of HMGB1. Interestingly, DNA bending by HMGB1 lacking the acidic C-tail (HMGB1ΔC) is much less affected by histone H1, but oxidization rendered DNA bending by HMGB1ΔC and HMGB1 equally prone for inhibition by histone H1. Possible consequences of histone H1-mediated inhibition of DNA bending by HMGB1 of different redox state for the functioning of chromatin are discussed.
- MeSH
- Cysteine genetics metabolism MeSH
- Histones chemistry genetics metabolism MeSH
- Rats MeSH
- Models, Molecular MeSH
- Mutation MeSH
- Nucleosomes MeSH
- Oxidation-Reduction MeSH
- HMGB1 Protein chemistry genetics metabolism MeSH
- DNA, Superhelical metabolism MeSH
- Protein Binding MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Research Support as Topic MeSH
- Rats MeSH
- Humans MeSH
- Tumor Suppressor Proteins metabolism MeSH
- Tumor Suppressor Protein p53 chemistry metabolism MeSH
- Promoter Regions, Genetic immunology MeSH
- HMGB1 Protein chemistry MeSH
- Binding Sites MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
Background: Psoriasis vulgaris is a chronic autoimmune disease associated with systemic inflammation. Increased levels of numerous cytokines, chemokines, growth factors, and other molecules were found in the skin and in the circulation of psoriatic patients. Alarmins, also known as danger signals, are intracellular proteins, which are released to an extracellular space after infection or damage. They are the markers of cell destructive processes. Objective: The aim of the present study was to evaluate the suitability of selected alarmins (HMGB1, IL-33, S100A7, and S100A12) as potential biomarkers of severity of psoriasis and to explore possible relationships between these proteins for the purpose of better understanding their roles in the immunopathology of psoriasis. Methods: The serum levels of selected alarmins were measured in 63 psoriatic patients and 95 control individuals. The levels were assessed by the ELISA technique using commercial kits. The data were statistically processed with MedCalc version 19.0.5. Results: In psoriatic patients, we found significantly increased levels of HMGB1 (p < 0.05), IL-33 (p < 0.01), S100A7 (p < 0.0001), and S100A12 (p < 0.0001). In addition, we found a significant relationship between HMGB1 and S100A7 (Spearman's rho = 0.276, p < 0.05) in the patients and significant relationship between HMGB1 and IL-33 in the controls (Spearman's rho = 0.416, p < 0.05). We did not find any relationship between observed alarmins and the disease severity. Conclusions: The alarmins HMGB1, IL-33, S100A7, and S100A12 were significantly elevated in the serum of patients, which states the hypothesis that they play specific roles in the immunopathology of psoriasis. However, we have not yet found a relationship between observed alarmins and the disease severity. The discovery of the relationship between HMGB1 and S100A7 is a novelty that should be studied in the future to further clarify its role and importance.
- MeSH
- Alarmins blood MeSH
- Adult MeSH
- Interleukin-33 blood MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- HMGB1 Protein blood MeSH
- S100A12 Protein blood MeSH
- S100 Calcium Binding Protein A7 blood MeSH
- Psoriasis immunology MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Severity of Illness Index MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- MeSH
- DNA Adducts chemistry MeSH
- Amino Acids chemistry MeSH
- Antineoplastic Agents chemistry MeSH
- Cisplatin chemistry MeSH
- Research Support as Topic MeSH
- Rats MeSH
- Models, Molecular MeSH
- HMGB1 Protein chemistry isolation & purification MeSH
- Cross-Linking Reagents MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
Topoisomerase IIalpha (topo IIalpha) is a nuclear enzyme involved in several critical processes, including chromosome replication, segregation and recombination. Previously we have shown that chromosomal protein HMGB1 interacts with topo IIalpha, and stimulates its catalytic activity. Here we show the effect of HMGB1 on the activity of the human topo IIalpha gene promoter in different cell lines. We demonstrate that HMGB1, but not a mutant of HMGB1 incapable of DNA bending, up-regulates the activity of the topo IIalpha promoter in human cells that lack functional retinoblastoma protein pRb. Transient over-expression of pRb in pRb-negative Saos-2 cells inhibits the ability of HMGB1 to activate the topo IIalpha promoter. The involvement of HMGB1 and its close relative, HMGB2, in modulation of activity of the topo IIalpha gene is further supported by knock-down of HMGB1/2, as evidenced by significantly decreased levels of topo IIalpha mRNA and protein. Our experiments suggest a mechanism of up-regulation of cellular expression of topo IIalpha by HMGB1/2 in pRb-negative cells by modulation of binding of transcription factor NF-Y to the topo IIalpha promoter, and the results are discussed in the framework of previously observed pRb-inactivation, and increased levels of HMGB1/2 and topo IIalpha in tumors.
- MeSH
- Transcriptional Activation MeSH
- Antigens, Neoplasm biosynthesis genetics MeSH
- DNA-Binding Proteins biosynthesis genetics MeSH
- DNA Topoisomerases, Type II biosynthesis genetics MeSH
- DNA chemistry metabolism MeSH
- CCAAT-Binding Factor metabolism MeSH
- Financing, Organized MeSH
- Humans MeSH
- Mutagenesis MeSH
- Cell Line, Tumor MeSH
- Promoter Regions, Genetic MeSH
- HMGB1 Protein genetics chemistry metabolism MeSH
- HMGB2 Protein metabolism MeSH
- Retinoblastoma Protein metabolism MeSH
- Aged MeSH
- Up-Regulation MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
Extracellular HMGB1 protein is known to induce inflammatory responses leading to an inflammatory storm. The outbreak of the Severe Acute Respiratory Syndrome COVID-19 due to the SARS-CoV-2 virus has resulted in a huge health concern worldwide. Recent data revealed that plasma/serum HMGB1 levels of patients suffering from inflammation-mediated disorders-such as COVID-19, cancer, and autoimmune disorders-correlate positively with disease severity and vice versa. A late release of HMGB1 in sepsis suggests the existence of a wide therapeutic window for treating sepsis. Rapid and accurate methods for the detection of HMGB1 levels in plasma/serum are, therefore, of great importance for monitoring the occurrence, treatment success, and survival prediction of patients with inflammation-mediated diseases. In this review, we briefly explain the role of HMGB1 in the cell, and particularly the involvement of extracellular HMGB1 (released from the cells) in inflammation-mediated diseases, with an emphasis on COVID-19. The current assays to measure HMGB1 levels in human plasma-Western blotting, ELISA, EMSA, and a new approach based on electrochemical immunosensors, including some of our preliminary results-are presented and thoroughly discussed.
- MeSH
- Biosensing Techniques MeSH
- COVID-19 * blood diagnosis MeSH
- Immunoassay MeSH
- Humans MeSH
- Prognosis MeSH
- HMGB1 Protein * blood MeSH
- SARS-CoV-2 MeSH
- Sepsis * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
HMGB1 is an architectural protein in chromatin, acting also as a signaling molecule outside the cell. Recent reports from several laboratories provided evidence that a number of both the intracellular and extracellular functions of HMGB1 may depend on redox-sensitive cysteine residues of the protein. In this study we demonstrate that redox state of HMGB1 can significantly modulate the ability of the protein to bind and bend DNA, as well as to promote DNA end-joining. We also report a high affinity binding of histone H1 to hemicatenated DNA loops and DNA minicircles. Finally, we show that reduced HMGB1 can readily displace histone H1 from DNA, while oxidized HMGB1 has limited capacity for H1 displacement. Our results suggested a novel mechanism for the HMGB1-mediated modulation of histone H1 binding to DNA. Possible biological consequences of linker histones H1 replacement by HMGB1 for the functioning of chromatin are discussed.
- MeSH
- Chromatin genetics metabolism MeSH
- Gene Expression MeSH
- Genetic Vectors chemistry MeSH
- Histones genetics metabolism MeSH
- DNA, Concatenated genetics metabolism MeSH
- DNA, Circular genetics metabolism MeSH
- Rats MeSH
- Humans MeSH
- Oxidation-Reduction MeSH
- HMGB1 Protein genetics metabolism MeSH
- Recombinant Proteins genetics metabolism MeSH
- Cattle MeSH
- Protein Binding MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Cattle MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Autism is a disorder of neural development characterized by impairments in communication, social interaction, restricted interests and repetitive behavior. The etiology of autism is poorly understood, the evidence indicates that inflammation may play a key role. In autism a high prevalence of gastrointestinal disturbances is reported, that are linked to a low-grade chronic inflammation of the intestinal mucosa. High mobility group box 1 protein (HMGB1) is an intranuclear protein that can be passively released from necrotic cells or actively secreted under inflammatory conditions as alarmin or late proinflammatory cytokine. The objective of this study was to measure plasma levels of HMGB1 in individuals with autism and to analyze their association with gastrointestinal symptoms. The study involved 31 subjects with low-functioning autistic disorder aged 2-22 years and 16 healthy controls. Plasma HMGB1 levels were significantly higher in individuals with autism than in controls (13.8+/-11.7 ng/ml vs. 7.90+/-4.0 ng/ml, p<0.02). In subjects with plasma HMGB1 levels higher than 11 ng/ml severe forms of GI disorders were more prevalent (83.3 %) than in subjects with lower levels (38.9 %, p<0.04). Results of the study support the involvement of the systemic low-grade inflammation in the pathomechanisms of autism and its possible association with GI symptoms.
- MeSH
- Autistic Disorder blood complications MeSH
- Biomarkers blood MeSH
- Child MeSH
- Gastrointestinal Diseases blood etiology MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Child, Preschool MeSH
- HMGB1 Protein blood MeSH
- Case-Control Studies MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
High mobility group box 1 (HMGB1), a nuclear protein, can be secreted by stimulated cells or released from damaged cells. It is recognized as a late mediator of sepsis, but its extracellular occurrence has primarily been studied on the systemic level. Acute and chronic diseases of the gastrointestinal tract, however, have usually been connected with immediate local cell damage. We present local and systemic findings of HMGB1 in Escherichia coli O55-caused infection, in relation to inflammatory cytokines, using a pig gnotobiotic infection model. High levels of HMGB1 were detected in the intestine of those piglets that suffered from infection (fever, anorexia, and diarrhea), as compared to their E. coli 055-infected counterparts that thrived. These local changes were also reflected at the systemic level and related to inflammatory cytokines. Based on our findings of high levels of HMGB1 in the intestinal content of the infection-suffering gnotobiotic piglets, its concurrent presence with inflammatory cytokines, and the published literature, we propose that the detection and analysis of HMGB1 levels in feces can be a non-invasive method of clinical evaluation of the severity of enteric infections.
- MeSH
- Bacterial Translocation * MeSH
- Cytokines blood MeSH
- Enteropathogenic Escherichia coli isolation & purification physiology MeSH
- Feces chemistry MeSH
- Germ-Free Life MeSH
- Escherichia coli Infections diagnosis microbiology MeSH
- Swine MeSH
- HMGB1 Protein analysis blood MeSH
- Intestines metabolism microbiology MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
