Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation

Abstract

High mobility group box 1 (HMGB1) is a multifunctional nuclear protein, probably known best as a prototypical alarmin or damage-associated molecular pattern (DAMP) molecule when released from cells. However, HMGB1 has multiple functions that depend on its location in the nucleus, in the cytosol, or extracellularly after either active release from cells, or passive release upon lytic cell death. Movement of HMGB1 between cellular compartments is a dynamic process induced by a variety of cell stresses and disease processes, including sepsis, trauma, and hemorrhagic shock.Location of HMGB1 is intricately linked with its function and is regulated by a series of posttranslational modifications. HMGB1 function is also regulated by the redox status of critical cysteine residues within the protein, and is cell-type dependent. This review highlights some of the mechanisms that contribute to location and functions of HMGB1, and focuses on some recent insights on important intracellular effects of HMGB1 during sepsis and trauma. K E Y W O R D S AIM2, autophagy, caspase-11, DAMPs, pyroptosis 2 NUCLEAR-TO-CYTOPLASM SHUTTLING OF HMGB1 HMGB1 consists of 215 aa residues, and contains 2 HMG DNAbinding domains, designated as A and B boxes, together with a negatively charged C-terminal acidic region. 14 Two nuclear localization sites (NLSs), one located in the A box (aa 28-44) and one in the B box (aa 179-185), control the nuclear localization of HMGB1 under homeostatic states. 14 Posttranslational modifications of NLS sites, including acetylation, phosphorylation, and methylation, regulate the ability of HMGB1 to translocate to the cytoplasm during cellular stress.Once in the cytoplasm HMGB1 can affect multiple inflammatory responses, and can be actively released into the extracellular space and circulation.

Ontogeny of inter‐alpha inhibitor protein (IAIP) expression in human brain

“…However, considering that much of the IAIP immunohistochemical expression appears to be mainly located in the nucleus, it remains possible that IAIPs could perform their function within the nucleus. Therefore, although we cannot be certain of the implications of our findings, we speculate that the relatively large number of cells containing nuclear IAIPs in cerebral cortex throughout a wide range of developmental ages suggests that endogenous nuclear IAIPs could potentially have a role in nuclear regulation of gene expression and/or other essential nuclear processes similar to those of histones and/or the high‐mobility group box‐1 protein (Chen, Nakada, et al, ; Deng, Scott, Fan, & Billiar, ; Tolsma & Hansen, ). In addition, the potential exists that IAIPs could be important binding partners for other nuclear proteins such as histones and the high‐mobility group box‐1 protein (Chaaban et al, ; Chen, Zhang, et al, ).…”

Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein

“…HMGB1, one of the key damage-associated molecular patterns, is an important late-acting inflammatory cytokine of sepsis that can be actively secreted by immune cells or passively released by injured or necrotic cells. It has been documented that HMGB1 is critically involved in host immune dysfunction and various diseases [30][31][32] , and it acts as a potent mediator of DC activation, maturation as well as survival [13][14][15][33][34][35] . In the present study, we investigated the proapoptotic effect of HMGB1 stimulation on DC2.4 cells in vitro, showing a time-dependent and dose-dependent manner.…”

High Mobility Group Box 1 and TLR4 Signaling Pathway in Gnotobiotic Piglets Colonized/Infected with L. amylovorus, L. mucosae, E. coli Nissle 1917 and S. Typhimurium

“…The alarmins are endogenous intracellular factors that are normally hidden from immune recognition, but in some conditions, such as cellular stress or injury, they can be released to the cell vicinity and sensed [1,5,6]. Circulating HMGB1 arises from a combination of both active secretion and passive release from cells of different lineages [7]. It can either promote beneficial tissue repair and provoke deleterious uncontrolled inflammation [8].…”