High Mobility Group Box 1 (HMGB1) Phenotypic Role Revealed with Stress

Tang, Daolin; Kang, Rui; Houten, Bennett Van; Zeh, Herbert J.; Billiar, Timothy R.; Lotze, Michael T.

doi:10.2119/molmed.2014.00063

Cited by 35 publications

(23 citation statements)

References 54 publications

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“…High mobility group box proteins bind to all immunogenic nucleic acids and can function as universal sentinels for nucleic acid–mediated innate immune responses, promoting activation of Toll‐like receptors (TLRs) 3/7/9 by their cognate nucleic acids . A key protein in the family, high mobility group box 1 (HMGB1), translocates from the nucleus to other cellular compartments, where it has a broad range of functions . Recent studies indicate that HMGB1 function depends on the redox status of cysteines at locations 23,45 (in A box domain) and 106 (in B box domain) .…”

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confidence: 99%

Redox‐dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice

et al. 2017

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Sterile liver inflammation, such as liver ischemia reperfusion, hemorrhagic shock after trauma and drug-induced liver injury is initiated and regulated by endogenous mediators including DNA and reactive oxygen species. Here we identify a novel mechanism for redox-mediated regulation of AIM2-inflammasome activation in hepatocytes after redox stress in mice, which occurs via interaction with cytosolic HMGB1. We show that in liver during hemorrhagic shock in mice, and in hepatocytes after hypoxia with reoxygenation, cytosolic HMGB1 associates with AIM2 and is required for activation of caspase-1 in response to cytosolic DNA. Activation of caspase-1 via AIM2 leads to subsequent hepatoprotective responses such as autophagy. HMGB1 binds to AIM2 at a non-DNA-binding site on the HIN-domain of AIM2 to facilitate inflammasome and caspase-1 activation in hepatocytes. Furthermore, binding of HMGB1 to AIM2 is stronger with fully-reduced all-thiol HMGB1 than with partially oxidized disulfide-HMGB1, and binding strength corresponds to caspase-1 activation. These data suggest HMGB1 redox status regulates AIM2 inflammasome activation. Conclusion Our findings suggest a novel and important mechanism for regulation of AIM2 inflammasome activation in hepatocytes during redox stress. Our study may suggest broader implications for how this and other inflammasomes are activated and how their activation is regulated during cell stress, as well as the mechanisms of inflammasome regulation in non-immune cell types.

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confidence: 99%

Redox‐dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice

et al. 2017

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“…Several genetic animal models of HMGB1 have recently been created to examine the physiological and pathological roles of HMGB1 in health and disease. The phenotype of HMGB1 conditional knockout mice is complex and even paradoxical (Ge et al, 2014; Huang et al, 2013a, 2014; Huebener et al, 2014; Kang et al, 2013b; Tang et al, 2014; Yanai et al, 2013). Future work investigating the details of HMGB1 location, structure, modification, and partners will uncover the secrets of HMGB1’s multiple functions.…”

Section: Discussionmentioning

confidence: 99%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

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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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“…In addition, HMGB1 deficiency increases genome instability with telomere shortening, which contributes to tumorigenesis [170, 184, 185]. Our studies demonstrate that HMGB1 is generally a positive regulator of autophagy [186–192], although an HMGB1-independent autophagy pathway exists [193, 194]. Loss of HMGB1 in cells results in autophagy dysfunction, which may cause genome instability, inflammation, and subsequent tumorigenesis.…”

Section: Damps At the Crossroads Of Ageing And Cancermentioning

confidence: 92%

DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’

Huang

Xie

Sun

et al. 2015

Ageing Research Reviews

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125

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Ageing is a complex and multifactorial process characterized by the accumulation of many forms of damage at the molecular, cellular, and tissue level with advancing age. Ageing increases the risk of the onset of chronic inflammation-associated diseases such as cancer, diabetes, stroke, and neurodegenerative disease. In particular, ageing and cancer share some common origins and hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury, reprogrammed metabolism, and degradation system impairment (including within the ubiquitin-proteasome system and the autophagic machinery). Recent advances indicate that damage-associated molecular pattern molecules (DAMPs) such as high mobility group box 1, histones, S100, and heat shock proteins play location-dependent roles inside and outside the cell. These provide interaction platforms at molecular levels linked to common hallmarks of ageing and cancer. They can act as inducers, sensors, and mediators of stress through individual plasma membrane receptors, intracellular recognition receptors (e.g., advanced glycosylation end product-specific receptors, AIM2-like receptors, RIG-I-like receptors, and NOD1-like receptors, and toll-like receptors), or following endocytic uptake. Thus, the DAMP Hypothesis is novel and complements other theories that explain the features of ageing. DAMPs represent ideal biomarkers of ageing and provide an attractive target for interventions in ageing and age-associated diseases.

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High Mobility Group Box 1 (HMGB1) Phenotypic Role Revealed with Stress

Cited by 35 publications

References 54 publications

Redox‐dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice

Redox‐dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice

HMGB1 in health and disease

DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’

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