High mobility group box 1 (HMGB1) is named for its electrophoretic mobility on polyacrylamide gels when it was first identified in calf thymus in 1973. HMGB1 plays a critical role in the stress response not only inside the cell as a DNA chaperone and cell death regulator, but also outside the cell as the prototypic damage-associated molecular pattern molecule. The physiological and pathological role of HMGB1 in health and disease has been widely studied for years. In this chapter, we will focus on the release and function of HMGB1 in cell death types such as apoptosis, autophagy, and necrosis.
Cell death is the cell’s process of losing its biological ability to carry out all the essential life processes. The Nomenclature Committee on Cell Death proposes several cell death classification criteria. According to morphological appearance, cell death is divided into apoptosis (type I), autophagy (type II), and necrosis (type III) [1, 2]. According to enzymological qualities, cell death is divided into several subtypes depending on the involvement or noninvolvement of nuclei or distinct protease classes such as caspases, calpains, cathepsins, and transglutaminases. According to immunological characteristics, cell death is divided into immunogenic or tolerogenic cell death . For example, apoptosis is generally considered nonimmunogenic cell death, whereas necrosis is considered immunogenic cell death. In addition, cell death can be classified into regulated or accidental cell death based on functional aspects . Accidental cell death is caused by unexpected and accidental cell damage (e.g., ischemic and trauma), whereas regulated cell death is mediated by an expected program in response to different stimuli. The list of regulated cell death subtypes is rapidly increasing and includes anoikis, autophagic cell death, apoptosis, cornification, entosis, ferroptosis, mitotic catastrophe, necroptosis, netosis, parthanatos, and pyroptosis . Cell death is essential for a plethora of physiological processes, and its deregulation is implicated in several human diseases such as infections, neurodegeneration, cancer, autoimmunity, and ischemic disease [5-7]. During the past few decades, a number of important concepts regarding the regulation of cell death and its roles in human health and disease have arisen. Understanding the molecular mechanisms and signaling pathways of cell death is crucial for identifying new diagnostic and therapeutic targets.
Compared to pathogen-associated molecular pattern molecules (PAMPs), which are generated from the components of foreign pathogens such as bacteria and viruses, damage-associated molecular pattern molecules (DAMPs) are endogenous or self-molecules that are secreted, released, or undergo surface exposure by dead, dying, or injured cells [8-12]. Both PAMPs and DAMPs are mainly recognized by pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) to mediate the inflammatory, immunity, and metabolism response. The release and activity of DAMPs during cell death can determine whether cell death is immunogenic or tolerogenic . Thus, DAMPs are suitable emergent targets for cell-death-associated immune therapy.
High mobility group box 1 (HMGB1) is named for its electrophoretic mobility on polyacrylamide gels when it was first identified in calf thymus in 1973 . As an extremely conserved protein, HMGB1 originated before the divergence of the protostomes and deuterostomes, approximately 525 million years ago . HMGB1 shares 100% amino acid sequence identity between mice and rats, and a 99% homology between rodents and humans [16-18]. The homolog of mammalian HMGB1 has been reported for several species such as
2. HMGB1 structure and function
Human HMGB1 consists of 215 amino acid residues and has two L-shaped DNA-binding domains (HMG A box [9-79aa], HMG B box [95-163aa]) and a shorter C-terminal tail (186-215aa) . Both A- and B-box domains are necessary for efficient DNA bending and flexure. HMGB1 binds to DNA without apparent sequence specificity. HMGB1 normally locates in the nucleus due to two nuclear-localization signals (NLS): NLS1 (28-44aa) and NLS2 (179-185aa) . In contrast, HMGB1 contains nuclear-emigration signals in DNA-binding domains, which contributes to extranuclear HMGB1 during stress in a nuclear exportin chromosome-region maintenance 1-dependent manner. In addition to DNA, HMGB1 can bind a number of proteins involved in multiple biologic processes. For example, HMGB1 binds to RAGE, TLR4, and p53 by residues 150-183, 89-108, and 7-74, which mediates cell migration , cytokine production , and gene transcription , respectively. The recombinant B box protein exhibits proinflammatory activity, whereas the recombinant A box protein displays anti-inflammatory activity , although the potential mechanism remains unknown. The C terminus is composed of 30 acidic amino acid residues and is able to regulate DNA binding/bending by intramolecular interaction with the A- and B- box [29, 30] or by intermolecular interaction with histones (e.g., H1 and H3) [31, 32]. Additionally, residues 201-205 in the C-terminal acidic tail region contribute to the antibacterial activity of recombinant HMGB1 . Hence, the structural basis of HMGB1 determines its biological function.
2.2. Intracellular HMGB1
2.2.1. Nuclear HMGB1
HMGB1 translocates between the cytoplasm and the nucleus, but normally stays in the nucleus in most cells and tissues. Nuclear HMGB1 is the structural protein of chromatin and orchestrates a number of nuclear events by its DNA chaperone activity as follows: (1) Nucleosome stability and sliding. As basic unit of chromatin, nucleosome contains a short length of DNA wrapped around a core of histone proteins. HMGB1 and histone H1 can bind to linker DNA between successive nucleosomes in the chromatin fiber . H1 stabilizes nucleosome with less mobility, whereas HMGB1 relaxes nucleosome and makes chromatin more accessible at the distorted site [35, 36]. (2) Nucleosome number and genome chromatinization. Loss of HMGB1 in mammalian and yeast cells leads to 20-30% less histones and nucleosomes and more RNA transcripts . (3) Nuclear catastrophe and nucleosome release. Conditional knockout of HMGB1 in the pancreas causes nuclear oxidative injury and proinflammatory nucleosome release, which mediates sterile inflammation . (4) DNA bending and binding. HMGB1 binds to DNA with structure-specificity, but not sequence-specificity . After binding DNA, the major function of HMGB1 is to bend and change DNA conformation by unwinding , looping , or compacting DNA . This DNA chaperone activity of HMGB1 is implicated in the regulation of gene transcription , DNA repair , DNA replication , V(D)J recombination , gene delivery , and gene transfer . (5) Telomere homeostasis. Loss of HMGB1 in yeast and mammalian cells inhibits telomerase activity, decreases telomere length, and increases DNA damage and chromosomal instability .
2.2.2. Cytosolic HMGB1
Several cell types (e.g., fibroblasts , thymocytes ), and tissue types (e.g., liver, kidney, heart, and lung)  have normal cytosolic HMGB1 expression. The ratio of nuclear to cytoplasmic HMGB1 is about 30:1 . Importantly, the translation of HMGB1 from the nucleus to the cytosol, including mitochondria and lysosomes, are observed in response to various stressors (e.g., cytokines, chemokines, heat, hypoxia, oxidative stress, and oncogenes). Although the function of cytosolic HMGB1 still remains poorly studied, HMGB1 may act as a positive regulator of mitochondrial quality in an autophagy-dependent and autophagy-independent manner [53, 54], which will be discussed later in the “Autophagy” section. In addition to autophagy, cytosolic HMGB1 is involved in the regulation of unconventional secretory pathways based on mass spectrometry-mediated binding partner analysis . In one study, several HMGB1-binding partners in nuclear and cytosol fraction were identified in several cancer cells . Among them, nine of the cytosolic HMGB1-binding proteins were related to protein translocation and secretion. In particular, immunoprecipitation analysis further confirmed four cytosolic HMGB1-binding proteins, including annexin A2, myosin IC isoform a, myosin-9, and Ras-related protein Rab10 . These proteins are directly implicated in the process of unconventional protein secretion. Further studies are needed to define the function of cytosolic HMGB1 in unconventional protein secretion. In addition to nuclear and cytosolic HMGB1, intracellular HMGB1 presents on cell surface membranes and regulates neurite outgrowth , platelet activation [57, 58], cell differentiation , erythroid maturation , adhesion , and innate immunity .
2.3. Extracellular HMGB1
HMGB1 is released in two different ways. On the one hand, HMGB1 can be actively secreted by normal cells, especially immune and endothelial cells [63, 64]. On the other hand, HMGB1 can be passively released by dead, dying, or injured cells in response to autophagic cell death , apoptosis [66, 67], necrosis , necroptosis [69, 70], netosis , and pyroptosis . Oxidative stress refers to elevated intracellular levels of reactive oxygen species (ROS) that play a central role in the regulation of HMGB1 secretion and release, although the actual mechanism of action remains ambiguous . Once released, HMGB1 acts as a cytokine, chemokine, and growth factor that is implicated in multiple biological processes including inflammation, immunity, migration, invasion, metabolism, proliferation, differentiation, antimicrobial defense, angiogenesis, tissue regeneration, death, autophagy, senescence, and efferocytosis. Extracellular HMGB1 plays important roles in the pathogenesis of human disease and is a potential therapy target in infection and sterile inflammation [74-76]. Several factors can affect HMGB1 activity in different experimental settings. For example, RAGE  and TLRs [78, 79] are positive receptors in macrophages and fibroblasts, whereas CD24  and T cell immunoglobulin mucin 3 [81, 82] are negative receptors of HMGB1-mediated signaling in macrophages and dendritic cells (DCs). In addition to receptors, HMGB1 can be directly taken up and mediate the inflammatory and metabolism response [83, 84]. Ultra-pure HMGB1 (free from contaminating bacterial proteins and nucleic acids) exhibits very low immune activity in macrophages. In contrast, extracellular HMGB1 is in fact a “sticky” protein and a synergistic immune effect is observed between HMGB1 and PAMPs (e.g., lipopolysaccharide), DAMPs (e.g., DNA), and other molecules (e.g., cytokines, chemokine, and IgG) in multiple cells . Thus, serum and plasma components (e.g., immunoglobulins, phospholipids, thrombomodulin, and proteoglycans) can interfere with HMGB1 detection by enzyme-linked immunosorbent assay . Another important factor affecting HMGB1 activity is its redox status . HMGB1 contains three conserved redox-sensitive cysteine residues: C23, C45, and C106. Reduced all-thiol-HMGB1 only exhibits chemokine activity, whereas disulfide-HMGB1 displays only cytokine activity, and oxidized HMGB1 has neither in immune cells . In addition, reduced HMGB1 induces autophagy, whereas oxidized HMGB1 triggers apoptosis in cancer cells . This redox status of HMGB1 also affects the affinity between HMGB1 and its receptors . A recent study demonstrates that HMGB1 is specifically cleaved by caspase-1 but not other caspases during inflammasome activation . Collectively, the release and activity of HMGB1 is context-dependent.
3. HMGB1 regulates cell death
3.1. Mechanism of HMGB1-mediated autophagy regulation
Autophagy, including macroautophagy, microautophagy, and chaperone-mediated autophagy, is a highly conserved degradation process in organisms from yeasts to plants and animals . The well-studied form of autophagy is macroautophagy (hereafter referred to as autophagy). As a complex dynamic process, autophagy is composed of the formation and maturation of three major membrane structures: the phagophore, autophagosome, and autolysosome . Briefly, the phagophore originates from multiple membrane resources and engulfs the cytosolic materials, which leads to the formation of a closed autophagosome with a double membrane. Of note, microtubule-associated protein light chain 3 (LC3)-II is a widely used autophagosome marker . Finally, autophagosomes fuse with lysosomes to form autolysosomes, which results in degradation of the engulfed material, including LC3-II, by lysosomal enzymes into elementary pieces that can be used for protein synthesis and energy production. Thus, autophagy is a programmed cell survival pathway in response to intracellular and extracellular stress . However, excessive or impaired autophagy can cause cell death, indicating a dual role of autophagy in cell survival and cell death. In particular, autosis is an Na+, K+-ATPase-dependent form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia–ischemia . The process of autophagy is controlled by multiple posttranslational modifications of the autophagy-related gene (Atg) family and shares regulators derived from other cell death pathways .
HMGB1 promotes autophagy in a location- and modification-dependent manner. Nuclear HMGB1 regulates heat shock protein β-1 (HSPB1) expression at a transactional level . The protein expression of HSPB1, but not other heat shock proteins, is significantly inhibited in HMGB1 knockout or knockdown cells. Both HMGB1 and HSPB1 regulate mitochondrial selective autophagy, namely mitophagy, following mitochondrial injury . Like other ATGs, it was recently suggested that HMGB1-independent autophagy exists in the regulation of mitochondrial quality, including the mitochondrial DNA damage response . Cytosolic HMGB1 is a Beclin-1 binding protein . HMGB1 C23S and C45S mutants lose their ability to bind Beclin-1 and therefore cannot promote autophagy . The binding of HMGB1 with Beclin-1 is positively regulated by unc-51-like kinase 1  mitogen-activated kinase-like protein , and nucleus accumbens-1 . In contrast, p53 , SNCA/α-synuclein , lysosomal thiol reductase , miR34A , and miR22  negatively regulate HMGB1-mediated autophagy by disrupting HMGB1-Beclin-1 complex formation. Moreover, activation of poly [ADP-ribose] polymerase 1 (PARP1) is required for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced ADP-ribosylation of HMGB1 and subsequent HMGB1-Beclin-1 complex formation in cancer cells . Extracellular reduced HMGB1, but not oxidized HMGB1, significantly induced autophagy in cancer cells in a RAGE-dependent manner . This process may sustain anaerobic energy production during tumor growth and development . Collectively, these findings suggest an HMGB1-dependent autophagic pathway at multiple levels in response to stress. However, HMGB1-independent autophagy may exist in several organs, although the underlying mechanism of its action remains obscure .
3.2. Mechanism of HMGB1-mediated apoptosis regulation
Apoptosis is the process of programmed cell death and includes classical “extrinsic” and “intrinsic” pathways and nonclassical T and natural killer cell-mediated cytolytic pathways. The extrinsic pathway is primarily mediated by the binding of a ligand to a transmembrane death receptor (DR). DRs are members of the TNF receptor gene superfamily, including FasR, TNFR1, lymphotoxin receptor, DR3, and DR4/DR5 . In addition to DRs, dependence receptors mediate apoptosis by monitoring the absence of certain trophic factors or the presence of anti-trophic factors . The intrinsic pathway for apoptosis involves activation of a mitochondrial pathway including altering mitochondrial permeability and subsequent release of mitochondrial proteins such as cytochrome c and second mitochondrial-derived activator of caspases . The process of apoptosis is tightly regulated by the Bcl-2, caspase, and nuclease families [112-114]. Caspases are a family of endoproteases linking inflammation and cell death. Initiator caspases (e.g., caspases-8 and -9) activate executioner caspases (e.g., caspases-3, -6, and -7) that mediate the cleavage of key structural proteins such as PARP1. However, caspase-independent apoptosis may exist by translocation of apoptosis-inducing factor [115, 116] and endonuclease G  from the mitochondria to the nucleus, or activation of Omi/HTRA2 (a mitochondrial serine protease) . Remarkably, several caspases (e.g., caspase-1, -4, -5, and -12 in humans; caspase-1, -11, and -12 in mice) are critical mediators of innate immune responses partly by activation of inflammasome, but not activation of the apoptosis pathway.
Intracellular HMGB1 is generally an anti-apoptotic protein in response to several apoptotic stimuli such as ultraviolet radiation, CD95, TRAIL, caspase-8, and Bax . Knockdown of HMGB1 increases drug sensitivity in cancer cells . Mechanically, HMGB1 plays transcriptional-dependent (e.g., regulation of Bcl-2 family protein expression) and transcriptional-independent roles (e.g., regulation of autophagy and p53 location) in the regulation of apoptosis. For example, inhibition of HMGB1-mediated autophagy can increase caspase activity . In addition to caspases, several non-caspase proteases such as calpain (Ca2+-dependent proteases) may play a role in the execution of apoptosis. Interestingly, HMGB1 deletion can enhance calpain activity and trigger cleavage of Beclin-1 and ATG5 . Thus, HMGB1 is an important regulator of the cross talk between apoptosis and autophagy.
3.3. Mechanism of HMGB1-mediated necrosis regulation
Necrosis includes accidental and regulated necrosis . Partially, the term “necroptosis” has recently been used to describe regulated necrosis when cells lack the capacity to activate caspase . Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL) [127, 128], and can be inhibited by small molecule inhibitors necrostatin 1 and necrosulfonamide [129, 130] . The fundamental causes of necrosis include calcium overload, ROS generation, cellular energy depletion, and membrane lipid injury . PARP is a protein family involved in a number of cellular processes such as DNA repair and programmed cell death. Induced overactivation of PARP1 can lead to adenosine triphosphate (ATP) depletion and subsequent necrosis . The process of necrosis ends with the leaking out of enzymes from lysosomes to digest cell components that are associated with HMGB1 release.
4. HMGB1 release in cell death
4.1. Mechanism of HMGB1 release in autophagy
Autophagic cell death is not only a morphologic notion such as cell death associated with autophagosomes and autolysosomes, but also a functional description that excessive autophagy can cause cell death. Induction of autophagy facilitates both active secretion and passive release of HMGB1. For example, the release of HMGB1 is significantly increased in response to epidermal growth factor (EGF) receptor-targeted diphtheria toxin (DT-EGF)-induced autophagic cell death . In contrast, suppression of ATG5, ATG7, or ATG12 expression by RNA interference (RNAi) inhibits autophagy and subsequent HMGB1 release after treatment with DT-EGF in cancer cells . In addition, ATG5-dependent autophagy promotes HMGB1 secretion in fibroblasts and macrophages after treatment with Hank’s balanced salt solution and lipopolysaccharide [97, 133]. Antioxidant (e.g., N-acetyl-L-cysteine) inhibits the cytosolic translocation and release of HMGB1 in starvation-induced autophagy . In contrast, ROS and knockdown of superoxide dismutases (SOD)-1 and SOD2 by RNAi promotes cytosolic HMGB1 expression and extracellular release . These findings suggest that oxidative stress is involved in autophagy-mediated HMGB1 release.
4.2. Mechanism of HMGB1 release in apoptosis
An early study indicated that HMGB1 is released only by necrotic cells, but not apoptotic cells . However, recent studies demonstrated that activation of caspases and deoxyribonuclease (DNase) in apoptosis regulates HMGB1 release and activity in apoptosis. Caspase-3 and caspase-7 are important executioner caspases in apoptosis through amplified initiation signals from caspase-8 and caspase-9. Activation of caspase-3 and -7 induces mitochondrial complex 1 protein p75 NDUFS1 cleavage, which results in mitochondrial ROS production and subsequent HMGB1 release during apoptosis in DCs . Interestingly, the activity of released HMGB1 in apoptosis is impaired, which promotes immunological resistance due to its oxidized form . In addition to caspase-3 and -7, caspase-1 is responsible for HMGB1 cleavage and release in the response to pyroptosis in immune cells [72, 136, 137]. This caspase-1-mediated HMGB1 fragment can rescue apoptosis-induced immune tolerance in a RAGE-dependent manner . Thus, different caspases can determine HMGB1 release and action in apoptosis and pyroptosis.
DNase is responsible for DNA fragmentation during cell death. Activation of DNA endonuclease (DNase-gamma) contributes to the degradation of DNA into nucleosomal units in apoptosis, whereas activation of DNase I and II facilitates degradation of DNA in necrosis . The release of HMGB1 in apoptosis is triggered by DNase-gamma-mediated nucleosomal DNA fragmentation [139, 140]. Thus, inhibition of DNase gamma activity by small molecular compound DR396 can significantly diminish HMGB1 release in response to apoptotic stimuli [139, 140].
4.3. Mechanism of HMGB1 release in necrosis
The nuclear enzyme PARP1, which catalyzes the synthesis of the biopolymer poly(ADP-ribose), exhibits an essential role in the DNA damage response and genomic stability. However, overactivation of PARP1 may deplete the stores of cellular NAD+, which results in ATP depletion and subsequent necrosis . In fact, HMGB1 release in necrosis is regulated by PARP1. Genetic and pharmacologic inhibition of PARP1 inhibits alkylating DNA damage agent-mediated necrosis as well as HMGB1 release . In addition to necrosis, activation of PARP1 also contributes to HMGB1 translocation and release in autophagy and inflammation [106, 143]. Interestingly, loss of HMGB1 in tissue and cells accelerates DNA damage that results in PARP1 overactivation . These findings suggest interplay between HMGB1 and PARP1 in response to cell death.
The RIP3-mediated signaling pathway is responsible for HMGB1 release in necroptosis. Upregulation of RIP3 expression
Cysteine cathepsins are lysosomal proteases with housekeeping functions that also initiate a specific cell death pathway termed lysosomal cell death. This type of cell death includes morphological features of necrosis and apoptosis . Cathepsin B, a critical lysosomal cysteine protease, mediates HMGB1 release following
5. Concluding remarks
HMGB1 is a member of family containing the evolutionarily conserved HMG box domains. The function of HMGB1 depends on its cellular location. Besides its functions in the nucleus and cytosol, HMGB1 plays a critical role in extracellular signaling associated with multiple biological processes. Both intracellular and extracellular HMGB1 are involved in the regulation of types of cell death such as apoptosis, necrosis, and autophagy. Intracellular HMGB1 regulates cell death in both transactional-dependent or transactional-independent manners. In many cases, HMGB1 is a negative regulator of apoptosis and necrosis, but a positive regulator of autophagy. In addition, the release and activity of HMGB1 in cell death is context-dependent, which may cause immunogenic cell death or tolerogenic cell death. Future studies are needed to define the upstream and downstream signaling of HMGB1 in the regulation of cell death; clarify the interplay and cooperative role of HMGB1 and other DAMPs in the cell-death-associated microenvironment; and develop new therapeutic strategies for targeting HMGB1 in cell-death-associated disorders.
We apologize to the researchers who were not referenced due to space limitations. We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by the USA National Institutes of Health (R01CA160417 and R01GM115366 to D.T.) and a 2013 Pancreatic Cancer Action Network-AACR Career Development Award (Grant Number 13-20-25-TANG). Work performed in support of findings reviewed in this manuscript was aided by core support of the University of Pittsburgh Cancer Institute (P30CA047904).
Kroemer, G., Galluzzi, L., Vandenabeele, P., Abrams, J., Alnemri, E.S., Baehrecke, E.H., Blagosklonny, M.V., El-Deiry, W.S., Golstein, P., Green, D.R., Hengartner, M., Knight, R.A., Kumar, S., Lipton, S.A., Malorni, W., Nunez, G., Peter, M.E., Tschopp, J., Yuan, J., Piacentini, M., Zhivotovsky, B., Melino, G. (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ16, 3-11.
Galluzzi, L., Vitale, I., Abrams, J.M., Alnemri, E.S., Baehrecke, E.H., Blagosklonny, M.V., Dawson, T.M., Dawson, V.L., El-Deiry, W.S., Fulda, S., Gottlieb, E., Green, D.R., Hengartner, M.O., Kepp, O., Knight, R.A., Kumar, S., Lipton, S.A., Lu, X., Madeo, F., Malorni, W., Mehlen, P., Nunez, G., Peter, M.E., Piacentini, M., Rubinsztein, D.C., Shi, Y., Simon, H.U., Vandenabeele, P., White, E., Yuan, J., Zhivotovsky, B., Melino, G., Kroemer, G. (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ19, 107-120.
Green, D.R., Ferguson, T., Zitvogel, L., Kroemer, G. (2009) Immunogenic and tolerogenic cell death. Nat Rev Immunol9, 353-363.
Galluzzi, L., Bravo-San Pedro, J.M., Vitale, I., Aaronson, S.A., Abrams, J.M., Adam, D., Alnemri, E.S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E.H., Bazan, N.G., Bertrand, M.J., Bianchi, K., Blagosklonny, M.V., Blomgren, K., Borner, C., Bredesen, D.E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F.K., Chandel, N.S., Cheng, E.H., Chipuk, J.E., Cidlowski, J.A., Ciechanover, A., Dawson, T.M., Dawson, V.L., De Laurenzi, V., De Maria, R., Debatin, K.M., Di Daniele, N., Dixit, V.M., Dynlacht, B.D., El-Deiry, W.S., Fimia, G.M., Flavell, R.A., Fulda, S., Garrido, C., Gougeon, M.L., Green, D.R., Gronemeyer, H., Hajnoczky, G., Hardwick, J.M., Hengartner, M.O., Ichijo, H., Joseph, B., Jost, P.J., Kaufmann, T., Kepp, O., Klionsky, D.J., Knight, R.A., Kumar, S., Lemasters, J.J., Levine, B., Linkermann, A., Lipton, S.A., Lockshin, R.A., Lopez-Otin, C., Lugli, E., Madeo, F., Malorni, W., Marine, J.C., Martin, S.J., Martinou, J.C., Medema, J.P., Meier, P., Melino, S., Mizushima, N., Moll, U., Munoz-Pinedo, C., Nunez, G., Oberst, A., Panaretakis, T., Penninger, J.M., Peter, M.E., Piacentini, M., Pinton, P., Prehn, J.H., Puthalakath, H., Rabinovich, G.A., Ravichandran, K.S., Rizzuto, R., Rodrigues, C.M., Rubinsztein, D.C., Rudel, T., Shi, Y., Simon, H.U., Stockwell, B.R., Szabadkai, G., Tait, S.W., Tang, H.L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E.F., et al. (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ22, 58-73.
Ashkenazi, A., Salvesen, G. (2014) Regulated cell death: signaling and mechanisms. Annu Rev Cell Dev Biol30, 337-356.
Linkermann, A., Stockwell, B.R., Krautwald, S., Anders, H.J. (2014) Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol14, 759-767.
Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., Vandenabeele, P. (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol15, 135-147.
Zitvogel, L., Kepp, O., Kroemer, G. (2010) Decoding cell death signals in inflammation and immunity. Cell140, 798-804.
Bianchi, M.E. (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol81, 1-5.
Rubartelli, A., Lotze, M.T. (2007) Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol28, 429-436.
Tang, D., Kang, R., Coyne, C.B., Zeh, H.J., Lotze, M.T. (2012) PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol Rev249, 158-175.
Zhang, Q., Kang, R., Zeh, H.J., 3rd, Lotze, M.T., Tang, D. (2013) DAMPs and autophagy: cellular adaptation to injury and unscheduled cell death. Autophagy9, 451-458.
Hou, W., Zhang, Q., Yan, Z., Chen, R., Zeh Iii, H.J., Kang, R., Lotze, M.T., Tang, D. (2013) Strange attractors: DAMPs and autophagy link tumor cell death and immunity. Cell death & disease4, e966.
Goodwin, G.H., Sanders, C., Johns, E.W. (1973) A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem38, 14-19.
Sharman, A.C., Hay-Schmidt, A., Holland, P.W. (1997) Cloning and analysis of an HMG gene from the lamprey Lampetra fluviatilis: gene duplication in vertebrate evolution. Gene184, 99-105.
Gariboldi, M., De Gregorio, L., Ferrari, S., Manenti, G., Pierotti, M.A., Bianchi, M.E., Dragani, T.A. (1995) Mapping of the Hmg1 gene and of seven related sequences in the mouse. Mamm Genome6, 581-585.
Ferrari, S., Ronfani, L., Calogero, S., Bianchi, M.E. (1994) The mouse gene coding for high mobility group 1 protein (HMG1). J Biol Chem269, 28803-28808.
Wen, L., Huang, J.K., Johnson, B.H., Reeck, G.R. (1989) A human placental cDNA clone that encodes nonhistone chromosomal protein HMG-1. Nucleic Acids Res17, 1197-1214.
Bustin, M. (2001) Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem Sci26, 152-153.
Giavara, S., Kosmidou, E., Hande, M.P., Bianchi, M.E., Morgan, A., d'Adda di Fagagna, F., Jackson, S.P. (2005) Yeast Nhp6A/B and mammalian Hmgb1 facilitate the maintenance of genome stability. Curr Biol15, 68-72.
Wu, Q., Zhang, W., Pwee, K.H., Kumar, P.P. (2003) Cloning and characterization of rice HMGB1 gene. Gene312, 103-109.
Kang, R., Chen, R., Zhang, Q., Hou, W., Wu, S., Cao, L., Huang, J., Yu, Y., Fan, X.G., Yan, Z., Sun, X., Wang, H., Wang, Q., Tsung, A., Billiar, T.R., Zeh, H.J., 3rd, Lotze, M.T., Tang, D. (2014) HMGB1 in health and disease. Mol Aspects Med40, 1-116.
Bianchi, M.E., Falciola, L., Ferrari, S., Lilley, D.M. (1992) The DNA binding site of HMG1 protein is composed of two similar segments (HMG boxes), both of which have counterparts in other eukaryotic regulatory proteins. Embo J11, 1055-1063.
Bonaldi, T., Talamo, F., Scaffidi, P., Ferrera, D., Porto, A., Bachi, A., Rubartelli, A., Agresti, A., Bianchi, M.E. (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. Embo J22, 5551-5560.
Huttunen, H.J., Fages, C., Kuja-Panula, J., Ridley, A.J., Rauvala, H. (2002) Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res62, 4805-4811.
Yang, H., Hreggvidsdottir, H.S., Palmblad, K., Wang, H., Ochani, M., Li, J., Lu, B., Chavan, S., Rosas-Ballina, M., Al-Abed, Y., Akira, S., Bierhaus, A., Erlandsson-Harris, H., Andersson, U., Tracey, K.J. (2010) A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci U S A107, 11942-11947.
Rowell, J.P., Simpson, K.L., Stott, K., Watson, M., Thomas, J.O. (2012) HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53 transactivation domain interaction, regulated by the acidic tail. Structure20, 2014-2024.
Li, J., Kokkola, R., Tabibzadeh, S., Yang, R., Ochani, M., Qiang, X., Harris, H.E., Czura, C.J., Wang, H., Ulloa, L., Warren, H.S., Moldawer, L.L., Fink, M.P., Andersson, U., Tracey, K.J., Yang, H. (2003) Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med9, 37-45.
Wang, Q., Zeng, M., Wang, W., Tang, J. (2007) The HMGB1 acidic tail regulates HMGB1 DNA binding specificity by a unique mechanism. Biochem Biophys Res Commun360, 14-19.
Stros, M. (1998) DNA bending by the chromosomal protein HMG1 and its high mobility group box domains. Effect of flanking sequences. J Biol Chem273, 10355-10361.
Ueda, T., Chou, H., Kawase, T., Shirakawa, H., Yoshida, M. (2004) Acidic C-tail of HMGB1 is required for its target binding to nucleosome linker DNA and transcription stimulation. Biochemistry43, 9901-9908.
Sheflin, L.G., Fucile, N.W., Spaulding, S.W. (1993) The specific interactions of HMG 1 and 2 with negatively supercoiled DNA are modulated by their acidic C-terminal domains and involve cysteine residues in their HMG 1/2 boxes. Biochemistry32, 3238-3248.
Gong, W., Li, Y., Chao, F., Huang, G., He, F. (2009) Amino acid residues 201-205 in C-terminal acidic tail region plays a crucial role in antibacterial activity of HMGB1. J Biomed Sci16, 83.
Carballo, M., Puigdomenech, P., Palau, J. (1983) DNA and histone H1 interact with different domains of HMG 1 and 2 proteins. Embo J2, 1759-1764.
Cato, L., Stott, K., Watson, M., Thomas, J.O. (2008) The interaction of HMGB1 and linker histones occurs through their acidic and basic tails. J Mol Biol384, 1262-1272.
Travers, A.A. (2003) Priming the nucleosome: a role for HMGB proteins? EMBO Rep4, 131-136.
Celona, B., Weiner, A., Di Felice, F., Mancuso, F.M., Cesarini, E., Rossi, R.L., Gregory, L., Baban, D., Rossetti, G., Grianti, P., Pagani, M., Bonaldi, T., Ragoussis, J., Friedman, N., Camilloni, G., Bianchi, M.E., Agresti, A. (2011) Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output. PLoS Biol9, e1001086.
Kang, R., Zhang, Q., Hou, W., Yan, Z., Chen, R., Bonaroti, J., Bansal, P., Billiar, T.R., Tsung, A., Wang, Q., Bartlett, D.L., Whitcomb, D.C., Chang, E.B., Zhu, X., Wang, H., Lu, B., Tracey, K.J., Cao, L., Fan, X.G., Lotze, M.T., Zeh, H.J., 3rd, Tang, D. (2014) Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology146, 1097-1107.
Yu, S.S., Li, H.J., Goodwin, G.H., Johns, E.W. (1977) Interaction of non-histone chromosomal proteins HMG1 and HMG2 with DNA. Eur J Biochem78, 497-502.
Yoshida, M., Makiguchi, K., Chida, Y., Shimura, K. (1984) Unwinding of DNA by nonhistone protein HMG1 and HMG2. Nucleic Acids Symp Ser, 181-184.
Paull, T.T., Haykinson, M.J., Johnson, R.C. (1993) The nonspecific DNA-binding and -bending proteins HMG1 and HMG2 promote the assembly of complex nucleoprotein structures. Genes Dev7, 1521-1534.
Javaherian, K., Liu, J.F., Wang, J.C. (1978) Nonhistone proteins HMG1 and HMG2 change the DNA helical structure. Science199, 1345-1346.
Stros, M., Ozaki, T., Bacikova, A., Kageyama, H., Nakagawara, A. (2002) HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J Biol Chem277, 7157-7164.
Liu, Y., Prasad, R., Wilson, S.H. (2010) HMGB1: roles in base excision repair and related function. Biochim Biophys Acta1799, 119-130.
Song, M.J., Hwang, S., Wong, W., Round, J., Martinez-Guzman, D., Turpaz, Y., Liang, J., Wong, B., Johnson, R.C., Carey, M., Sun, R. (2004) The DNA architectural protein HMGB1 facilitates RTA-mediated viral gene expression in gamma-2 herpesviruses. J Virol78, 12940-12950.
Zhang, M., Swanson, P.C. (2009) HMGB1/2 can target DNA for illegitimate cleavage by the RAG1/2 complex. BMC Mol Biol10, 24.
Kim, I.D., Shin, J.H., Kim, S.W., Choi, S., Ahn, J., Han, P.L., Park, J.S., Lee, J.K. (2012) Intranasal delivery of HMGB1 siRNA confers target gene knockdown and robust neuroprotection in the postischemic brain. Mol Ther20, 829-839.
Ueda, T., Shirakawa, H., Yoshida, M. (2002) Involvement of HMGB1 and HMGB2 proteins in exogenous DNA integration reaction into the genome of HeLa S3 cells. Biochim Biophys Acta1593, 77-84.
Polanska, E., Dobsakova, Z., Dvorackova, M., Fajkus, J., Stros, M. (2012) HMGB1 gene knockout in mouse embryonic fibroblasts results in reduced telomerase activity and telomere dysfunction. Chromosoma121, 419-431.
Einck, L., Soares, N., Bustin, M. (1984) Localization of HMG chromosomal proteins in the nucleus and cytoplasm by microinjection of functional antibody fragments into living fibroblasts. Exp Cell Res152, 287-301.
Guillet, F., Tournefier, A., Denoulet, P., Capony, J.P., Kerfourn, F., Charlemagne, J. (1990) High levels of HMG1-2 protein expression in the cytoplasm and nucleus of hydrocortisone sensitive amphibian thymocytes. Biol Cell69, 153-160.
Kuehl, L., Salmond, B., Tran, L. (1984) Concentrations of high-mobility-group proteins in the nucleus and cytoplasm of several rat tissues. J Cell Biol99, 648-654.
Ito, H., Fujita, K., Tagawa, K., Chen, X., Homma, H., Sasabe, T., Shimizu, J., Shimizu, S., Tamura, T., Muramatsu, S., Okazawa, H. (2015) HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice. EMBO Mol Med7, 78-101.
Tang, D., Kang, R., Livesey, K.M., Kroemer, G., Billiar, T.R., Van Houten, B., Zeh, H.J., 3rd, Lotze, M.T. (2011) High-mobility group box 1 is essential for mitochondrial quality control. Cell Metab13, 701-711.
Lee, H., Shin, N., Song, M., Kang, U.B., Yeom, J., Lee, C., Ahn, Y.H., Yoo, J.S., Paik, Y.K., Kim, H. (2010) Analysis of nuclear high mobility group box 1 (HMGB1)-binding proteins in colon cancer cells: clustering with proteins involved in secretion and extranuclear function. J Proteome Res9, 4661-4670.
Merenmies, J., Pihlaskari, R., Laitinen, J., Wartiovaara, J., Rauvala, H. (1991) 30-kDa heparin-binding protein of brain (amphoterin) involved in neurite outgrowth. Amino acid sequence and localization in the filopodia of the advancing plasma membrane. J Biol Chem266, 16722-16729.
Maugeri, N., Franchini, S., Campana, L., Baldini, M., Ramirez, G.A., Sabbadini, M.G., Rovere-Querini, P., Manfredi, A.A. (2012) Circulating platelets as a source of the damage-associated molecular pattern HMGB1 in patients with systemic sclerosis. Autoimmunity45:584-587.
Fuentes, E., Rojas, A., Palomo, I. (2014) Role of multiligand/RAGE axis in platelet activation. Thromb Res133, 308-314.
Passalacqua, M., Zicca, A., Sparatore, B., Patrone, M., Melloni, E., Pontremoli, S. (1997) Secretion and binding of HMG1 protein to the external surface of the membrane are required for murine erythroleukemia cell differentiation. FEBS Lett400, 275-279.
Hanspal, M., Hanspal, J.S. (1994) The association of erythroblasts with macrophages promotes erythroid proliferation and maturation: a 30-kD heparin-binding protein is involved in this contact. Blood84, 3494-3504.
Parkkinen, J., Rauvala, H. (1991) Interactions of plasminogen and tissue plasminogen activator (t-PA) with amphoterin. Enhancement of t-PA-catalyzed plasminogen activation by amphoterin. J Biol Chem266, 16730-16735.
Ciucci, A., Gabriele, I., Percario, Z.A., Affabris, E., Colizzi, V., Mancino, G. (2011) HMGB1 and cord blood: its role as immuno-adjuvant factor in innate immunity. PLoS ONE6, e23766.
Wang, H., Bloom, O., Zhang, M., Vishnubhakat, J.M., Ombrellino, M., Che, J., Frazier, A., Yang, H., Ivanova, S., Borovikova, L., Manogue, K.R., Faist, E., Abraham, E., Andersson, J., Andersson, U., Molina, P.E., Abumrad, N.N., Sama, A., Tracey, K.J. (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science285, 248-251.
Yang, L., Xie, M., Yang, M., Yu, Y., Zhu, S., Hou, W., Kang, R., Lotze, M.T., Billiar, T.R., Wang, H., Cao, L., Tang, D. (2014) PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun5, 4436.
Thorburn, J., Horita, H., Redzic, J., Hansen, K., Frankel, A.E., Thorburn, A. (2009) Autophagy regulates selective HMGB1 release in tumor cells that are destined to die. Cell Death Differ16, 175-183.
Bell, C.W., Jiang, W., Reich, C.F., 3rd, Pisetsky, D.S. (2006) The extracellular release of HMGB1 during apoptotic cell death. Am J Physiol Cell Physiol291, C1318-1325.
Jiang, W., Bell, C.W., Pisetsky, D.S. (2007) The relationship between apoptosis and high-mobility group protein 1 release from murine macrophages stimulated with lipopolysaccharide or polyinosinic-polycytidylic acid. J Immunol178, 6495-6503.
Scaffidi, P., Misteli, T., Bianchi, M.E. (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature418, 191-195.
Duprez, L., Takahashi, N., Van Hauwermeiren, F., Vandendriessche, B., Goossens, V., Vanden Berghe, T., Declercq, W., Libert, C., Cauwels, A., Vandenabeele, P. (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity35, 908-918.
Zhang, A., Mao, X., Li, L., Tong, Y., Huang, Y., Lan, Y., Jiang, H. (2014) Necrostatin-1 inhibits Hmgb1-IL-23/IL-17 pathway and attenuates cardiac ischemia reperfusion injury. Transpl Int27, 1077-1085.
Mitroulis, I., Kambas, K., Chrysanthopoulou, A., Skendros, P., Apostolidou, E., Kourtzelis, I., Drosos, G.I., Boumpas, D.T., Ritis, K. (2011) Neutrophil extracellular trap formation is associated with IL-1beta and autophagy-related signaling in gout. PLoS ONE6, e29318.
Lu, B., Nakamura, T., Inouye, K., Li, J., Tang, Y., Lundback, P., Valdes-Ferrer, S.I., Olofsson, P.S., Kalb, T., Roth, J., Zou, Y., Erlandsson-Harris, H., Yang, H., Ting, J.P., Wang, H., Andersson, U., Antoine, D.J., Chavan, S.S., Hotamisligil, G.S., Tracey, K.J. (2012) Novel role of PKR in inflammasome activation and HMGB1 release. Nature488, 670-674.
Tang, D., Kang, R., Zeh, H.J., 3rd, Lotze, M.T. (2011) High-mobility group box 1, oxidative stress, and disease. Antioxid Redox Signal14, 1315-1335.
Andersson, U., Tracey, K.J. (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol29, 139-162.
Wang, H., Zhu, S., Zhou, R., Li, W., Sama, A.E. (2008) Therapeutic potential of HMGB1-targeting agents in sepsis. Expert Rev Mol Med10, e32.
Wang, H., Yang, H., Czura, C.J., Sama, A.E., Tracey, K.J. (2001) HMGB1 as a late mediator of lethal systemic inflammation. Am J Respir Crit Care Med164, 1768-1773.
Hori, O., Brett, J., Slattery, T., Cao, R., Zhang, J., Chen, J.X., Nagashima, M., Lundh, E.R., Vijay, S., Nitecki, D., et al. (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem270, 25752-25761.
Park, J.S., Svetkauskaite, D., He, Q., Kim, J.Y., Strassheim, D., Ishizaka, A., Abraham, E. (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem279, 7370-7377.
Tian, J., Avalos, A.M., Mao, S.Y., Chen, B., Senthil, K., Wu, H., Parroche, P., Drabic, S., Golenbock, D., Sirois, C., Hua, J., An, L.L., Audoly, L., La Rosa, G., Bierhaus, A., Naworth, P., Marshak-Rothstein, A., Crow, M.K., Fitzgerald, K.A., Latz, E., Kiener, P.A., Coyle, A.J. (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol8, 487-496.
Chen, G.Y., Tang, J., Zheng, P., Liu, Y. (2009) CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science323, 1722-1725.
Tang, D., Lotze, M.T. (2012) Tumor immunity times out: TIM-3 and HMGB1. Nat Immunol13, 808-810.
Chiba, S., Baghdadi, M., Akiba, H., Yoshiyama, H., Kinoshita, I., Dosaka-Akita, H., Fujioka, Y., Ohba, Y., Gorman, J.V., Colgan, J.D., Hirashima, M., Uede, T., Takaoka, A., Yagita, H., Jinushi, M. (2012) Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol13, 832-842.
Kang, R., Tang, D., Schapiro, N.E., Loux, T., Livesey, K.M., Billiar, T.R., Wang, H., Van Houten, B., Lotze, M.T., Zeh, H.J. (2014) The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. Oncogene33, 567-577.
Xu, J., Jiang, Y., Wang, J., Shi, X., Liu, Q., Liu, Z., Li, Y., Scott, M.J., Xiao, G., Li, S., Fan, L., Billiar, T.R., Wilson, M.A., Fan, J. (2014) Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis. Cell Death Differ21, 1229-1239.
Bianchi, M.E. (2009) HMGB1 loves company. J Leukoc Biol86, 573-576.
Urbonaviciute, V., Furnrohr, B.G., Weber, C., Haslbeck, M., Wilhelm, S., Herrmann, M., Voll, R.E. (2007) Factors masking HMGB1 in human serum and plasma. J Leukoc Biol81, 67-74.
Tang, D., Billiar, T.R., Lotze, M.T. (2012) A Janus tale of two active high mobility group box 1 (HMGB1) redox states. Mol Med18, 1360-1362.
Venereau, E., Casalgrandi, M., Schiraldi, M., Antoine, D.J., Cattaneo, A., De Marchis, F., Liu, J., Antonelli, A., Preti, A., Raeli, L., Shams, S.S., Yang, H., Varani, L., Andersson, U., Tracey, K.J., Bachi, A., Uguccioni, M., Bianchi, M.E. (2012) Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med209, 1519-1528.
Tang, D., Kang, R., Cheh, C.W., Livesey, K.M., Liang, X., Schapiro, N.E., Benschop, R., Sparvero, L.J., Amoscato, A.A., Tracey, K.J., Zeh, H.J., Lotze, M.T. (2010) HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene29, 5299-5310.
LeBlanc, P.M., Doggett, T.A., Choi, J., Hancock, M.A., Durocher, Y., Frank, F., Nagar, B., Ferguson, T.A., Saleh, M. (2014) An immunogenic peptide in the A-box of HMGB1 protein reverses apoptosis-induced tolerance through RAGE receptor. J Biol Chem289, 7777-7786.
Mizushima, N., Levine, B. (2010) Autophagy in mammalian development and differentiation. Nat Cell Biol12, 823-830.
Klionsky, D.J., Emr, S.D. (2000) Autophagy as a regulated pathway of cellular degradation. Science290, 1717-1721.
Mizushima, N., Yoshimori, T., Levine, B. (2010) Methods in mammalian autophagy research. Cell140, 313-326.
Kroemer, G., Marino, G., Levine, B. (2010) Autophagy and the integrated stress response. Mol Cell40, 280-293.
Liu, Y., Shoji-Kawata, S., Sumpter, R.M., Jr., Wei, Y., Ginet, V., Zhang, L., Posner, B., Tran, K.A., Green, D.R., Xavier, R.J., Shaw, S.Y., Clarke, P.G., Puyal, J., Levine, B. (2013) Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc Natl Acad Sci U S A110, 20364-20371.
Xie, Y., Kang, R., Sun, X., Zhong, M., Huang, J., Klionsky, D.J., Tang, D. (2015) Posttranslational modification of autophagy-related proteins in macroautophagy. Autophagy11, 28-45.
Tang, D., Kang, R., Livesey, K.M., Cheh, C.W., Farkas, A., Loughran, P., Hoppe, G., Bianchi, M.E., Tracey, K.J., Zeh, H.J., 3rd, Lotze, M.T. (2010) Endogenous HMGB1 regulates autophagy. J Cell Biol190, 881-892.
Huang, J., Ni, J., Liu, K., Yu, Y., Xie, M., Kang, R., Vernon, P., Cao, L., Tang, D. (2012) HMGB1 promotes drug resistance in osteosarcoma. Cancer Res72, 230-238.
Tang, D., Kang, R., Livesey, K.M., Cheh, C.W., Farkas, A., Loughran, P., Hoppe, G., Bianchi, M.E., Tracey, K.J., Zeh, H.J., 3rd, Lotze, M.T. (2010) Endogenous HMGB1 regulates autophagy. J Cell Biol190, 881-892.
Zhang, Y., Cheng, Y., Ren, X., Zhang, L., Yap, K.L., Wu, H., Patel, R., Liu, D., Qin, Z.H., Shih, I.M., Yang, J.M. (2012) NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response. Oncogene31, 1055-1064.
Livesey, K., Kang, R., Vernon, P., Buchser, W., Loughran, P., Watkins, S.C., Zhang, L., Manfredi, J.J., Zeh, H.J., Li, L., Lotze, M., Tang, D. (2012) p53/HMGB1 complexes regulate autophagy and apoptosis. Cancer Res72, 1996-2005.
Song, J.X., Lu, J.H., Liu, L.F., Chen, L.L., Durairajan, S.S., Yue, Z., Zhang, H.Q., Li, M. (2014) HMGB1 is involved in autophagy inhibition caused by SNCA/alpha-synuclein overexpression: a process modulated by the natural autophagy inducer corynoxine B. Autophagy10, 144-154.
Chiang, H.S., Maric, M. (2011) Lysosomal thiol reductase negatively regulates autophagy by altering glutathione synthesis and oxidation. Free Radic Biol Med51, 688-699.
Liu, K., Huang, J., Xie, M., Yu, Y., Zhu, S., Kang, R., Cao, L., Tang, D., Duan, X. (2014) MIR34A regulates autophagy and apoptosis by targeting HMGB1 in the retinoblastoma cell. Autophagy10, 442-452.
Li, X., Wang, S., Chen, Y., Liu, G., Yang, X. (2014) miR-22 targets the 3' UTR of HMGB1 and inhibits the HMGB1-associated autophagy in osteosarcoma cells during chemotherapy. Tumour Biol35, 6021-6028.
Yang, M., Liu, L., Xie, M., Sun, X., Yu, Y., Kang, R., Yang, L., Zhu, S., Cao, L., Tang, D. (2015) Poly-ADP-ribosylation of HMGB1 regulates TNFSF10/TRAIL resistance through autophagy. Autophagy, 11, 214-224.
Luo, Y., Yoneda, J., Ohmori, H., Sasaki, T., Shimbo, K., Eto, S., Kato, Y., Miyano, H., Kobayashi, T., Sasahira, T., Chihara, Y., Kuniyasu, H. (2014) Cancer usurps skeletal muscle as an energy repository. Cancer Res74, 330-340.
Sun, X., Tang, D. (2014) HMGB1-dependent and -independent autophagy. Autophagy10, 1873-1876.
Ashkenazi, A., Dixit, V.M. (1999) Apoptosis control by death and decoy receptors. Curr Opin Cell Biol11, 255-260.
Mehlen, P., Bredesen, D.E. (2011) Dependence receptors: from basic research to drug development. Sci Signal4, mr2.
Tait, S.W., Green, D.R. (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol11, 621-632.
Youle, R.J., Strasser, A. (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nature reviews. Molecular cell biology9, 47-59.
Samejima, K., Earnshaw, W.C. (2005) Trashing the genome: the role of nucleases during apoptosis. Nat Rev Mol Cell Biol6, 677-688.
Riedl, S.J., Shi, Y. (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol5, 897-907.
Susin, S.A., Lorenzo, H.K., Zamzami, N., Marzo, I., Snow, B.E., Brothers, G.M., Mangion, J., Jacotot, E., Costantini, P., Loeffler, M., Larochette, N., Goodlett, D.R., Aebersold, R., Siderovski, D.P., Penninger, J.M., Kroemer, G. (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature397, 441-446.
Daugas, E., Susin, S.A., Zamzami, N., Ferri, K.F., Irinopoulou, T., Larochette, N., Prevost, M.C., Leber, B., Andrews, D., Penninger, J., Kroemer, G. (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. Faseb J14, 729-739.
Li, L.Y., Luo, X., Wang, X. (2001) Endonuclease G is an apoptotic DNase when released from mitochondria. Nature412, 95-99.
Hegde, R., Srinivasula, S.M., Zhang, Z., Wassell, R., Mukattash, R., Cilenti, L., DuBois, G., Lazebnik, Y., Zervos, A.S., Fernandes-Alnemri, T., Alnemri, E.S. (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem277, 432-438.
Brezniceanu, M.L., Volp, K., Bosser, S., Solbach, C., Lichter, P., Joos, S., Zornig, M. (2003) HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma. Faseb J17, 1295-1297.
Kang, R., Zhang, Q., Zeh, H.J., 3rd, Lotze, M.T., Tang, D. (2013) HMGB1 in cancer: good, bad, or both? Clin Cancer Res19, 4046-4057.
Livesey, K.M., Kang, R., Vernon, P., Buchser, W., Loughran, P., Watkins, S.C., Zhang, L., Manfredi, J.J., Zeh, H.J., 3rd, Li, L., Lotze, M.T., Tang, D. (2012) p53/HMGB1 complexes regulate autophagy and apoptosis. Cancer Res72, 1996-2005.
Zhu, X., Messer, J.S., Wang, Y., Lin, F., Cham, C.M., Chang, J., Billiar, T.R., Lotze, M.T., Boone, D.L., Chang, E.B. (2015) Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation. J Clin Invest125, 1098-1110.
Huang, H., Nace, G.W., McDonald, K.A., Tai, S., Klune, J.R., Rosborough, B.R., Ding, Q., Loughran, P., Zhu, X., Beer-Stolz, D., Chang, E.B., Billiar, T., Tsung, A. (2014) Hepatocyte specific HMGB1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular HMGB1 in cellular protection. Hepatology59, 1984-1997.
Yanai, H., Matsuda, A., An, J., Koshiba, R., Nishio, J., Negishi, H., Ikushima, H., Onoe, T., Ohdan, H., Yoshida, N., Taniguchi, T. (2013) Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc Natl Acad Sci U S A110, 20699-20704.
Guerin, R., Arseneault, G., Dumont, S., Rokeach, L.A. (2008) Calnexin is involved in apoptosis induced by endoplasmic reticulum stress in the fission yeast. Mol Biol Cell19, 4404-4420.
Linkermann, A., Green, D.R. (2014) Necroptosis. N Engl J Med370, 455-465.
Li, J., McQuade, T., Siemer, A.B., Napetschnig, J., Moriwaki, K., Hsiao, Y.S., Damko, E., Moquin, D., Walz, T., McDermott, A., Chan, F.K., Wu, H. (2012) The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell150, 339-350.
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T., Kroemer, G. (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol11, 700-714.
Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G.D., Mitchison, T.J., Moskowitz, M.A., Yuan, J. (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol1, 112-119.
Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I.L., Korkina, O., Teng, X., Abbott, D., Cuny, G.D., Yuan, C., Wagner, G., Hedrick, S.M., Gerber, S.A., Lugovskoy, A., Yuan, J. (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol4, 313-321.
Zong, W.X., Thompson, C.B. (2006) Necrotic death as a cell fate. Genes Dev20, 1-15.
Ha, H.C., Snyder, S.H. (1999) Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A96, 13978-13982.
Dupont, N., Jiang, S., Pilli, M., Ornatowski, W., Bhattacharya, D., Deretic, V. (2011) Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1beta. Embo J30, 4701-4711.
Tang, D., Kang, R., Livesey, K.M., Zeh, H.J., 3rd, Lotze, M.T. (2011) High mobility group box 1 (HMGB1) activates an autophagic response to oxidative stress. Antioxid Redox Signal15, 2185-2195.
Kazama, H., Ricci, J.E., Herndon, J.M., Hoppe, G., Green, D.R., Ferguson, T.A. (2008) Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity29, 21-32.
Kamo, N., Ke, B., Ghaffari, A.A., Shen, X.D., Busuttil, R.W., Cheng, G., Kupiec-Weglinski, J.W. (2013) ASC/caspase-1/IL-1beta signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia/reperfusion injury. Hepatology58, 351-362.
Leblanc, P.M., Doggett, T.A., Choi, J., Hancock, M.A., Durocher, Y., Frank, F., Nagar, B., Ferguson, T.A., Saleh, M. (2014) An Immunogenic Peptide in the A-box of HMGB1 Reverses Apoptosis-Induced Tolerance Through RAGE. J Biol Chem. 289, 7777-7786.
Nagata, S., Nagase, H., Kawane, K., Mukae, N., Fukuyama, H. (2003) Degradation of chromosomal DNA during apoptosis. Cell Death Differ10, 108-116.
Yamada, Y., Fujii, T., Ishijima, R., Tachibana, H., Yokoue, N., Takasawa, R., Tanuma, S. (2011) DR396, an apoptotic DNase gamma inhibitor, attenuates high mobility group box 1 release from apoptotic cells. Bioorg Med Chem19, 168-171.
Yamada, Y., Fujii, T., Ishijima, R., Tachibana, H., Yokoue, N., Takasawa, R., Tanuma, S. (2011) The release of high mobility group box 1 in apoptosis is triggered by nucleosomal DNA fragmentation. Arch Biochem Biophys506, 188-193.
Zong, W.X., Ditsworth, D., Bauer, D.E., Wang, Z.Q., Thompson, C.B. (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev18, 1272-1282.
Ditsworth, D., Zong, W.X., Thompson, C.B. (2007) Activation of poly(ADP)-ribose polymerase (PARP-1) induces release of the pro-inflammatory mediator HMGB1 from the nucleus. J Biol Chem282, 17845-17854.
Yang, Z., Li, L., Chen, L., Yuan, W., Dong, L., Zhang, Y., Wu, H., Wang, C. (2014) PARP-1 mediates LPS-induced HMGB1 release by macrophages through regulation of HMGB1 acetylation. J Immunol193, 6114-6123.
Huang, H., Nace, G.W., McDonald, K.A., Tai, S., Klune, J.R., Rosborough, B.R., Ding, Q., Loughran, P., Zhu, X., Beer-Stolz, D., Chang, E.B., Billiar, T., Tsung, A. (2014) Hepatocyte specific HMGB1 deletion worsens the injury in liver ischemia/reperfusion: A role for intracellular HMGB1 in cellular protection. Hepatology59, 1984-1997.
Lau, A., Wang, S., Jiang, J., Haig, A., Pavlosky, A., Linkermann, A., Zhang, Z.X., Jevnikar, A.M. (2013) RIPK3-mediated necroptosis promotes donor kidney inflammatory injury and reduces allograft survival. Am J Transplant13, 2805-2818.
Murakami, Y., Matsumoto, H., Roh, M., Giani, A., Kataoka, K., Morizane, Y., Kayama, M., Thanos, A., Nakatake, S., Notomi, S., Hisatomi, T., Ikeda, Y., Ishibashi, T., Connor, K.M., Miller, J.W., Vavvas, D.G. (2014) Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ21, 270-277.
Aits, S., Jaattela, M. (2013) Lysosomal cell death at a glance. J Cell Sci126, 1905-1912.
Morinaga, Y., Yanagihara, K., Nakamura, S., Hasegawa, H., Seki, M., Izumikawa, K., Kakeya, H., Yamamoto, Y., Yamada, Y., Kohno, S., Kamihira, S. (2010) Legionella pneumophila induces cathepsin B-dependent necrotic cell death with releasing high mobility group box1 in macrophages. Respir Res11, 158.
Willingham, S.B., Bergstralh, D.T., O'Connor, W., Morrison, A.C., Taxman, D.J., Duncan, J.A., Barnoy, S., Venkatesan, M.M., Flavell, R.A., Deshmukh, M., Hoffman, H.M., Ting, J.P. (2007) Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe2, 147-159.
Duncan, J.A., Gao, X., Huang, M.T., O'Connor, B.P., Thomas, C.E., Willingham, S.B., Bergstralh, D.T., Jarvis, G.A., Sparling, P.F., Ting, J.P. (2009) Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. J Immunol 182, 6460-6469.