Invited reviewHMGB1 as biomarker and drug target
Graphical abstract
Introduction
High mobility group Box 1 protein (HMGB1) is a nuclear protein [30] that acts as a DNA chaperone and participates in a number of activities in the nucleus, including transcription, replication, DNA repair and nucleosome assembly [1], [9], [15], [86]. Besides its roles in the nucleus, HMGB1 can also translocate to the cytoplasm, where it can activate autophagy by interacting with beclin-1 [44], and to the extracellular medium, where it acts as a DAMP (Damage Associated Molecular Pattern) molecule that alerts nearby cells and the immune system to immediate danger, triggering inflammation [89]. The importance of HMGB1 in physiology and pathology is well illustrated by two facts:
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HMGB1 has 3 paralogs (proteins that share substantial sequence similarity) in mammals (HMGB2, 3, and 4), and yet Hmgb1-/- mice die during late gestation or within 24 h of birth [13]
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all multicellular animals have at least one gene closely related to HMGB1 (i.e. an orthologous gene, related by evolutionary ancestry), and unicellular eukaryotes and plants have more loosely related genes and proteins [92]. Notably, also the DAMP functions of extracellular HMGB1 are evolutionary ancient, having been documented in mollusks [54].
HMGB1 has emerged as one of the main mediators in both acute and chronic inflammation, and therefore plays a role in an impressive number of medical conditions [2]. In this review, we give an overview on HMGB1 as a pharmacological target, and we focus on its different isoforms and their respective roles in disease.
Section snippets
HMGB1 is a sophisticated danger signal with pleiotropic functions
HMGB1 can exit the cell through two different pathways: passive or active release. Soluble proteins leak passively from dead cells that lost their membrane integrity; thus, HMGB1 can be released by all dead cells, with the notable exception of apoptotic cells, which modify HMGB1 and/or their nuclear chromatin, to prevent HMGB1 leakage [89]. Beside its passive release, HMGB1 can also be actively secreted by cells under severe stress or by inflammatory cells in response to Pathogen-Associated
HMGB1 as a biomarker
HMGB1 is a multifunctional protein and the list of disorders in which it is involved is constantly growing. Here, we highlight the significance of the characterization of its post-translational modifications and the evaluation of their use as clinical biomarkers for multiple disorders.
HMGB1 inhibition by biologics
Several biologics have been developed in the past years in order to inhibit HMGB1 specifically, including antibodies, fragments of HMGB1 itself, and soluble receptors.
HMGB1 as a druggable target for small molecules
The proinflammatory functions of HMGB1 make it a suitable target in several pathological conditions characterized by an excessive inflammatory response. However, HMGB1 has several receptors, so targeting HMGB1 itself rather than its individual receptors appears most rational.
Concluding remarks and future perspectives
Since the discovery of its extracellular release, HMGB1 has been identified as a drug-target protein in multiple diseases and recently, as a target of aspirin, the most widely used drug worldwide, demonstrating the importance of this DAMP in the clinic and opening new perspective to improve current drugs. However, the targeting of such a structurally flexible and pharmacologically versatile protein is definitely not a simple matter. Structural studies led to the identification, at the atomistic
Conflict of interest statement
M.E. Bianchi is a co-inventor in multiple patents involving HMGB1 and is founder and part owner of HMGBiotech, a company that provides goods and services related to HMGB proteins. E. Vénéreau is partially supported by HMGBiotech and is a co-inventor in a patent involving HMGB1.
Acknowledgements
This work was supported by a grant from Associazione Italiana Ricerca sul Cancro to M.E. Bianchi (IG-14233) and Ministero della Salute to E. Vénéreau (GR-2011-02351814). G.M. and F.D.L. thank support by AIRC and Marie Curie Actions, FP7 People-COFUND (iCARE 2014 Reintegration fellowship, project number 16258).
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