High-mobility group box 1 protein (HMGB1) operates as an alarmin outside as well as inside cells
Introduction
Cells in all living organisms are constantly challenged by sterile or infectious stimuli that may cause cellular injury or death. The universal alarm system sensing danger-induced cellular stress utilizes preformed endogenous molecules termed alarmins or damage-associated molecular pattern molecules (DAMPs) for this communication [[1], [2], [3]]. These molecules display other intracellular tasks during homeostatic conditions, but when released extracellularly in response to danger signals they exert immunologic activity that promotes inflammation. The purpose of the discharge of alarmins is to arm cells by adjusting for challenged cellular homeostasis and to initiate repair mechanisms. However, alarmin release may also paradoxically cause tissue injury and organ dysfunction central in the pathogenesis of many acute and chronic diseases [[4], [5], [6]]. Targeting alarmins may conceivably offer a useful novel approach to therapy.
We here focus on the biology of high-mobility group box 1 protein (HMGB1) acting as a typical alarmin [[6], [7], [8]]. After translocation to the outside, HMGB1 operates as a warning signal that induces inflammation via two fundamentally separate means. Extracellular HMGB1 may, like many other alarmins and pathogen-derived mediators, bind directly to cell surface receptors on somatic and immune cells propagating intracellular signaling cascades that mediate inflammation [8,9]. Alternatively, HMGB1 may bind to a number of different soluble extracellular immune-activating molecules that will be endocytosed into the endolysosomal system as HMGB1-bound complexes [10,11]. Inside lysosomes HMGB1 has the capacity to disrupt the lysosome, which enables HMGB1-partner molecules to enter the cytosol [11,12]. The HMGB1-mediated cellular uptake thus enables molecular access to endosomal and cytoplasmic immune receptors reciprocal to HMGB1-partner molecules or to HMGB1 itself. The internalized proinflammatory molecules would not reach and encounter their intracellular sensors without the delivery by HMGB1 via mechanisms to be further outlined.
Section snippets
HMGB1 biology
HMGB1 is an evolutionarily highly preserved nuclear, non-histone DNA-binding protein named for its high electrophoretic mobility on polyacrylamide gels [8]. There are four different HMGBs in mammals, HMGB1-4, but HMGB1 is by far the most abundantly and most ubiquitously expressed [13]. It is an extremely mobile protein inside the cell nucleus, where it influences chromatin structure and enhances the accessibility of binding sites to regulatory elements like transcription factors and
Mechanisms for HMGB1 release
HMGB1 can be discharged to the cellular outside via active and passive routes occurring in both somatic and immune cells. Receptor-mediated HMGB1 release appearing in stimulated cells initially requires hyperacetylation of multiple lysines present in the two HMGB1 nuclear localization sites (NLS) forcing the nuclear HMGB1 to accumulate in the cytoplasm. HMGB1 constantly shuttles between the cytoplasm and the nucleus in a resting cell, but acetylation of lysines in the NLS prevents the nuclear
HMGB1 receptor systems
The list of published HMGB1-receptors described to elicit signal transduction due to extracellular HMGB1 ligation is remarkably long, most likely too long. At least 14 different receptor systems have been reported to be engaged by extracellular HMGB1 (reviewed in [8,9]). All of them were originally discovered as receptors for ligands unrelated to HMGB1. However, only two receptor systems, TLR4 and RAGE, have so far been extensively studied in carefully defined molecular systems and confirmed in
Sepsis
The proinflammatory activity of HMGB1 was first discovered in studies designed to identify novel mediators of sepsis [34]. Administration of lethal doses of endotoxin to mammals activates a biphasic cytokine response that can be divided into early and late kinetic profiles. The classical proinflammatory cytokine response develops early, with peak levels of TNF or IL-1 occurring within a few hours. HMGB1 release takes place significantly later, reaching a plateau 16 to 32 h after the onset of
Conclusions
The ubiquitous nuclear protein HMGB1 can be translocated to the outside of cells and propagate inflammation as an alarmin. The best characterized cell surface receptors for HMGB1-mediated immune functions are TLR4 and RAGE. Apart from operating on its own, HMGB1 also acts in strong synergy with several other potent inflammatory molecules including LPS, DNA, RNA, and IL-1. HMGB1 forms complexes with these mediators and transports them via RAGE-mediated endocytosis to the endolysosomal system.
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