Antimicrobial Activity of High-Mobility-Group Box 2: a New Function to a Well-Known Protein

Kuchler, Robert J.; Schroeder, Bjoern O.; Jaeger, Simon U.; Stange, Eduard F.; Wehkamp, Jan

doi:10.1128/aac.00805-13

Cited by 21 publications

(21 citation statements)

References 62 publications

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“…8a ). Hmgb2 , encoding a DNA-interacting protein with antimicrobial properties, was largely restricted to blood neutrophils 48 . Neutrophils from acutely inflamed lung and peritoneum upregulated Xbp1 and Nfkb1 , implicated in neutrophil effector responses and their control 49 , 50 .…”

Section: Resultsmentioning

confidence: 99%

The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments

et al. 2021

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Neutrophils are implicated in multiple homeostatic and pathological processes, but whether functional diversity requires discrete neutrophil subsets is not known. Here, we apply single-cell RNA sequencing to neutrophils from normal and inflamed mouse tissues. Whereas conventional clustering yields multiple alternative organizational structures, diffusion mapping plus RNA velocity discloses a single developmental spectrum, ordered chronologically. Termed here neutrotime, this spectrum extends from immature pre-neutrophils, largely in bone marrow, to mature neutrophils predominantly in blood and spleen. The sharpest increments in neutrotime occur during the transitions from pre-neutrophils to immature neutrophils and from mature marrow neutrophils to those in blood. Human neutrophils exhibit a similar transcriptomic pattern. Neutrophils migrating into inflamed mouse lung, peritoneum and joint maintain the core mature neutrotime signature together with new transcriptional activity that varies with site and stimulus. Together, these data identify a single developmental spectrum as the dominant organizational theme of neutrophil heterogeneity.

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Section: Resultsmentioning

confidence: 99%

The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments

et al. 2021

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“…Extracellular HMGB2 is increased in experimental and clinical acute lung injury (Ueno et al, 2004), suggesting a possible role for HMGB2 in tissue injury. In addition, extracellular HMGB2 has antimicrobial activity in intestinal tissue, but the mechanism remains unknown (Kuchler et al, 2013). The presence of serum anti-HMGB2 antibodies may contribute to inflammatory bowel disease (Takaishi et al, 2012), suggesting a possible role for extracellular HMGB2 in the regulation of autoimmunity.…”

Section: Introduction and Historical Backgroundmentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

801

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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“…Antimicrobial peptides (AMPs) are key effector molecules that protect the body from an overgrowth of pathogenic and commensal bacteria (1). AMPs show antimicrobial activity against many microbes, bacteria, fungi, and some viruses (2)(3)(4)(5). One of the most important and intensively studied groups of AMPs are defensins (2), a group of very small cationic peptides characterized by three intramolecular disulfide bridges (2,6).…”

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confidence: 99%

Bacterial Periplasmic Oxidoreductases Control the Activity of Oxidized Human Antimicrobial β-Defensin 1

et al. 2018

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The antimicrobial peptide human β-defensin 1 (hBD1) is continuously produced by epithelial cells in many tissues. Compared to other defensins, hBD1 has only minor antibiotic activity in its native state. After reduction of its disulfide bridges, however, it becomes a potent antimicrobial agent against bacteria, while the oxidized native form (hBD1ox) shows specific activity against Gram-negative bacteria. We show that the killing mechanism of hBD1ox depends on aerobic growth conditions and bacterial enzymes. We analyzed the different activities of hBD1 using mutants of lacking one or more specific proteins of their outer membrane, cytosol, or redox systems. We discovered that DsbA and DsbB are essential for the antimicrobial activity of hBD1ox but not for that of reduced hBD1 (hBD1red). Furthermore, our results strongly suggest that hBD1ox uses outer membrane protein FepA to penetrate the bacterial periplasm space. In contrast, other bacterial proteins in the outer membrane and cytosol did not modify the antimicrobial activity. Using immunogold labeling, we identified the localization of hBD1ox in the periplasmic space and partly in the outer membrane of However, in resistant mutants lacking DsbA and DsbB, hBD1ox was detected mainly in the bacterial cytosol. In summary, we discovered that hBD1ox could use FepA to enter the periplasmic space, where its activity depends on presence of DsbA and DsbB. HBD1ox concentrates in the periplasm in Gram-negative bacteria, which finally leads to bleb formation and death of the bacteria. Thus, the bacterial redox system plays an essential role in mechanisms of resistance against host-derived peptides such as hBD1.

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Antimicrobial Activity of High-Mobility-Group Box 2: a New Function to a Well-Known Protein

Cited by 21 publications

References 62 publications

The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments

The neutrotime transcriptional signature defines a single continuum of neutrophils across biological compartments

HMGB1 in health and disease

Bacterial Periplasmic Oxidoreductases Control the Activity of Oxidized Human Antimicrobial β-Defensin 1

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