Donald and Barbara Zucker School of Medicine Journal Articles Academic Works 2014 HMGB1 in health and disease R. Kang R. C. Chen Q. H. Zhang W. Hou S. Wu See next page for additional authors Follow this and additional works at: https://academicworks.medicine.hofstra.edu/articles Part of the Emergency Medicine Commons Recommended Citation Kang R, Chen R, Zhang Q, Hou W, Wu S, Fan X, Yan Z, Sun X, Wang H, Tang D, . HMGB1 in health and disease. 2014 Jan 01; 40():Article 533 [ p.]. Available from: https://academicworks.medicine.hofstra.edu/articles/533. Free full text article. This Article is brought to you for free and open access by Donald and Barbara Zucker School of Medicine Academic Works. It has been accepted for inclusion in Journal Articles by an authorized administrator of Donald and Barbara Zucker School of Medicine Academic Works. Authors R. Kang, R. C. Chen, Q. H. Zhang, W. Hou, S. Wu, X. G. Fan, Z. W. Yan, X. F. Sun, H. C. Wang, D. L. Tang, and +8 additional authors This article is available at Donald and Barbara Zucker School of Medicine Academic Works: https://academicworks.medicine.hofstra.edu/articles/533 NIH Public Access Author Manuscript Mol Aspects Med. Author manuscript; available in PMC 2015 December 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Mol Aspects Med. 2014 December ; 0: 1–116. doi:10.1016/j.mam.2014.05.001. HMGB1 in Health and Disease Rui Kang1,*, Ruochan Chen1, Qiuhong Zhang1, Wen Hou1, Sha Wu1, Lizhi Cao2, Jin Huang3, Yan Yu2, Xue-gong Fan4, Zhengwen Yan1,5, Xiaofang Sun6, Haichao Wang7, Qingde Wang1, Allan Tsung1, Timothy R. Billiar1, Herbert J. Zeh III1, Michael T. Lotze1, and Daolin Tang1,* 1Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA 2Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 3Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 4Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 5Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China 6Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Experimental Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, China 7Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA Abstract 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 © 2014 Elsevier Ltd. All rights reserved. *Correspondence to: Daolin Tang ([email protected]) and Rui Kang ([email protected]). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Kang et al. Page 2 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 NIH-PA Author Manuscript NIH-PA Author Manuscriptfrom apoptotic NIH-PA Author Manuscript 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. 1 Introduction and Historical Background In 1879, Walther Flemming, a trailblazing German cytologist, identified chromosomes using aniline dyes (Paweletz, 2001). We now know that chromosomes contain all genes that transfer well-defined characteristics from parents to offsprings. Chromosomes are actually packages of condensed chromatin, which is a nucleoprotein complex, residua of our archaeal past. The precise interaction between DNA and chromosomal protein regulates the structure, dynamics, and function of chromosomes, which in turn facilitates genomic stability and gene regulation (Andrews and Luger, 2011; Elgin and Weintraub, 1975; Stein et al., 1974). Histones, including H1, H2A, H2B, H3, and H4, are the predominant class of positively- charged chromosomal proteins (Campos and Reinberg, 2009). Histones tightly bind to negatively-charged DNA to condense it into a more compact structure, termed a nucleosome. A nucleosome is the basic repeating unit of chromatin with repetitive histone octamer units, which are typically wrapped with 147 base pairs of DNA. The second class of chromosomal proteins is composed of several relatively low-abundance, tissue-specific, high salt-urea insoluble proteins (Earnshaw and Mackay, 1994; Wakabayashi et al., 1974). These proteins include the nuclear matrix proteins, the chromosome scaffold protein, and the enzymes responsible for regulation of major DNA-associated events (e.g., replication, transcription, repair, and recombination). The third class of chromosomal proteins, and second most abundant, is the high mobility group (HMG) proteins including HMGB, HMGN, and HMGA. Compared with histones, HMG proteins have been highly conserved throughout evolution and loosely bind to chromatin without targeting individual DNA sequences but rather DNA structure (Bianchi and Beltrame, 1998; Einck and Bustin, 1985). Besides performing nuclear functions, several HMG proteins, including HMGB1 (Scaffidi et al., 2002; Wang et al., 1999), HMGB2 (Pusterla et al., 2009), and HMGN1 (Yang et al., 2012a) exert significant extracellular activity and function as damage-associated molecular pattern molecules (DAMPs). Recent genetic, biochemical, and cell biological analyses have greatly improved our understanding of the structure and function of HMG proteins in DNA- related processes, development, differentiation, aging, and cancer (Bianchi and Agresti, Mol Aspects Med. Author manuscript; available in PMC 2015 December 01. Kang et al. Page 3 2005; Bustin et al., 1990; Hock et al., 2007). In this review, we will briefly introduce the HMG protein members and focus on the physiological and pathological role of HMGB1 in NIH-PA Author Manuscript NIH-PA Author Manuscripthealth NIH-PA Author Manuscript and disease. We believe that understanding of the HMG family is a link to our evolutionary past and a deeper understanding the bridge to our future. 1.1 Discovery of the HMG Protein Ernest Johns from the Chester Beatty Research Institute, London is the pioneer of HMG research. In 1973, Ernest Johns and colleagues Graham Goodwin and Clive Sanders first isolated two groups of proteins from calf thymus chromatin by 0.35M NaCl extraction (Goodwin and Johns, 1973; Goodwin et al., 1973). One group of proteins was easily soluble in 10% trichloroacetic acid and migrated rapidly in polyacrylamide gel electrophoresis systems with no signs of aggregation. Based on its mobility, they called them “high-mobility group” proteins, namely HMG proteins (Goodwin et al., 1973). Partial fractionation of these HMG proteins by gel filtration revealed that they contained at least two proteins, namely protein 1 (HMG-1) and protein 2 (HMG-2). These two proteins are composed of over 55% acidic/basic amino acids with about 105 molecules of HMG-1 and -2 per cell nucleus (Goodwin and Johns, 1973; Goodwin et al., 1973). In contrast, the other group of proteins contained much fewer basic amino acids and migrated more slowly in polyacrylamide gel electrophoresis systems. They therefore called them “low-mobility group”