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Review
. 2019 Jul;106(1):161-169.
doi: 10.1002/JLB.3MIR1218-497R. Epub 2019 Apr 4.

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

Meihong Deng  1   2 , Melanie J Scott  1   2   3 , Jie Fan  1   2   4 , Timothy R Billiar  1   2   3
Affiliations
Review

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

Meihong Deng et al. J Leukoc Biol. 2019 Jul.

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.

Keywords: AIM2; DAMPs; autophagy; caspase-11; pyroptosis.

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Conflict of interest statement

Conflict of Interest

The authors declare no conflicts of interest.

Figures

Figure 1:
Figure 1:. Intracellular and extracellular roles for HMGB1 in LPS-mediated infection and sepsis.
LPS uptake into hepatocytes triggers HMGB1 mobilization from the nucleus, and active release via a caspase-11/gasdermin D-mediated pathway. Extracellular HMGB1 then facilitates LPS uptake into macrophages, endosomal/lysosomal rupture and release of HMGB1 and LPS into the cell cytosol, inducing caspase-11 and caspase-1 signaling and macrophage pyroptosis.
Figure 2:
Figure 2:. Regulation of autophagy/mitophagy by intracellular HMGB1.
HMBG1 interacts with AIM2 and double stranded DNA in response to redox stress and activates inflammasome and caspase-1, inducing autophagy/mitophagy via beclin1-mediated pathways. HMGB1 also displaces Bcl2 from its association with beclin1, allowing autophagy initiation. Displaced Bcl2 acts as a apoptosis inhibitor. Unassociated beclin1 can be more easily cleaved/degraded by calpain and other cleavage enzymes which increases apoptosis.
See this image and copyright information in PMC

References

    1. Einck L and Bustin M (1985) The intracellular distribution and function of the high mobility group chromosomal proteins. Exp Cell Res 156, 295–310. - PubMed
    1. Javaherian K, Liu JF, Wang JC (1978) Nonhistone proteins HMG1 and HMG2 change the DNA helical structure. Science 199, 1345–6. - PubMed
    1. Ferrari S, Ronfani L, Calogero S, Bianchi ME (1994) The mouse gene coding for high mobility group 1 protein (HMG1). J Biol Chem 269, 28803–8. - PubMed
    1. Gariboldi M, De Gregorio L, Ferrari S, Manenti G, Pierotti MA, Bianchi ME, Dragani TA (1995) Mapping of the Hmg1 gene and of seven related sequences in the mouse. Mamm Genome 6, 581–5. - PubMed
    1. Wen L, Huang JK, Johnson BH, Reeck GR (1989) A human placental cDNA clone that encodes nonhistone chromosomal protein HMG-1. Nucleic Acids Res 17, 1197–214. - PMC - PubMed

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