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The multifunctional protein HMGB1: 50 years of discovery

Nature Reviews Immunology volume 23, pages 824–841 (2023)Cite this article

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Abstract

Fifty years since the initial discovery of HMGB1 in 1973 as a structural protein of chromatin, HMGB1 is now known to regulate diverse biological processes depending on its subcellular or extracellular localization. These functions include promoting DNA damage repair in the nucleus, sensing nucleic acids and inducing innate immune responses and autophagy in the cytosol and binding protein partners in the extracellular environment and stimulating immunoreceptors. In addition, HMGB1 is a broad sensor of cellular stress that balances cell death and survival responses essential for cellular homeostasis and tissue maintenance. HMGB1 is also an important mediator secreted by immune cells that is involved in a range of pathological conditions, including infectious diseases, ischaemia–reperfusion injury, autoimmunity, cardiovascular and neurodegenerative diseases, metabolic disorders and cancer. In this Review, we discuss the signalling mechanisms, cellular functions and clinical relevance of HMGB1 and describe strategies to modify its release and biological activities in the setting of various diseases.

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Fig. 1: Timeline of breakthrough discoveries since HMGB1 was first identified.
Fig. 2: Signalling pathways of extracellular HMGB1.
Fig. 3: Structure and function of HMGB1.
Fig. 4: Interactions between lipopolysaccharide and HMGB1 in inflammation and coagulation.
Fig. 5: Interplay between HMGB1 and autophagy in cell death and inflammation.
Fig. 6: The role of HMGB1 in cancer biology and tumour immunity.

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Acknowledgements

The authors thank D. Primm for his critical reading of the manuscript. The authors appreciate all of the pioneers in the field and our colleagues who contributed to the discovery of the compartmental functions of HMGB1. The authors apologize if they were unable to cite all of the important references in this field owing to space limitations. Research by D.T. and R.K. was supported by grants from the National Institutes of Health (R01CA160417, R01CA229275 and R01CA211070). Support to M.T.L. was provided by the Alliance for Cancer Cell and Gene Therapy (Gamma Delta T cells).

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  1. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

    Daolin Tang, Rui Kang & Herbert J. Zeh

  2. Departments of Surgery, Immunology and Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Michael T. Lotze

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Glossary

Autophagy

A lysosome-dependent cellular process by which cells break down and recycle their own cellular components, including aged or dysfunctional proteins and organelles, as well as invading microorganisms.

Cytokine storm

A severe and excessive release of cytokines, which can result in a systemic and potentially life-threatening inflammatory response.

Damage-associated molecular pattern

(DAMP). Part of a group of endogenous molecules that are released in response to cellular injury or damage to alert the immune system.

Disseminated intravascular coagulation

A medical condition in which abnormal blood clotting occurs throughout the small blood vessels of the body.

Endotoxin lethality

The ability of bacterial lipopolysaccharides, also known as endotoxins, to cause death in organisms.

Endotoxin tolerance

The adaptive process by which the immune system becomes less responsive to the effects of bacterial lipopolysaccharides, also known as endotoxins.

Immunogenic cell death

(ICD). A type of cell death that is characterized by the release of intracellular components, such as DAMPs, into the surrounding environment to trigger an immune response.

Neutrophil extracellular traps

(NETs). A type of cellular defence mechanism used by neutrophils to capture and eliminate invading microorganisms such as bacteria and fungi.

Sequential organ failure assessment

A standardized tool used to assess the severity of organ dysfunction (respiratory, cardiovascular, liver, coagulation, kidney and nervous system) in critically ill patients.

Sterile inflammation

A type of immune response that occurs in response to damage or injury to cells or tissues, without the presence of a pathogenic microorganism.

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Tang, D., Kang, R., Zeh, H.J. et al. The multifunctional protein HMGB1: 50 years of discovery. Nat Rev Immunol 23, 824–841 (2023). https://doi.org/10.1038/s41577-023-00894-6

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