J Bacteriol Virol.  2013 Jun;43(2):148-154. 10.4167/jbv.2013.43.2.148.

Current Understanding of HMGB1-mediated Autophagy

• Kwak MS
• Shin JS

• KMID: 2168685
• DOI: http://doi.org/10.4167/jbv.2013.43.2.148

Abstract

Reactive oxygen species (ROS) is an oxidative stress to which cells respond by activating various defense mechanisms or cell death. Autophagy associated with oxidative stress response is a process to degrade and recycle macro-molecule as well as organelles in eukaryotic cells. HMGB1, a ubiquitous nuclear protein, is actively released in eukaryotic cells under oxidative stress. HMGB1 plays an important role as regulator of autophagy in nuclear, cytosolic and extracellular level. Nuclear HMGB1 regulates the expression of heat shock protein beta-1 (HSPB1), which is critical for dynamic intracellular trafficking during autophagy and mitophagy. Cytoplasmic HMGB1 can bind to a beclin 1 by the intramolecular disulfide bridge using cysteine 23 and 45, which dissociates its inhibitory partner Bcl-2 and induces autophagy. Extracellular HMGB1 binds to receptor for advanced glycation endproducts (RAGE) which inhibits mammalian target of rapamycin (mTOR) and then promotes the formation of the belin1-Ptdlns3KC3 complex. Furthermore, endogenous HMGB1 is an intrinsic regulator of autophagy, and it enhances chemoresistance in diverse cancer cells. Here, we review recent reports suggesting a novel mechanism of diverse cancer cell resistance to therapy facilitated by HMGB1-mediated autophagy.

Keyword

HMGB1; Autophagy; ROS; Drug resistance

MeSH Terms

Advanced Glycosylation End Product-Specific Receptor
Autophagy
Cell Death
Cysteine
Cytoplasm
Cytosol
Defense Mechanisms
Drug Resistance
Eukaryotic Cells
HMGB1 Protein
HSP27 Heat-Shock Proteins
Mitochondrial Degradation
Nuclear Proteins
Organelles
Oxidative Stress
Reactive Oxygen Species
Receptors, Immunologic
Sirolimus
Cysteine
HMGB1 Protein
HSP27 Heat-Shock Proteins
Nuclear Proteins
Reactive Oxygen Species
Receptors, Immunologic
Sirolimus

Figure

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  Figure 1. The structure and function of HMGB1. (A) HMGB1 is composed of three domains: two DNA binding domains (the A and B boxes) and a negatively charged carboxyl terminus. Three cysteines are encoded at position 23, 45, and 106. (B) HMGB1 is present in almost all of eukaryotic cells. In nucleus, HMGB1 plays roles in the DNA replication, recombination, transcription, and repair. In cytoplasm, HMGB1 regulates the balance between autophagy and apoptosis. Extracellular HMGB1 mediates the response to inflammation, differentiation, migration, proliferation, and development.

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  Figure 2. The release of HMGB1. (A) HMGB1 is actively secreted in response to exogenous and endogenous inflammatory stimuli. This translocation is stimulated by post-translational modification. (B) HMGB1 is also passively released by necrotic or apoptotic cells death caused by injury.

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  Figure 3. The role of HMGB1 in autophagy. Endogenous HMGB1 competes with Bcl2-Beclin1 complex. The intramolecular disulfide bridge (C23 and C45) of HMGB1 is required for binding to beclin1 and regulate autophagosome formation. The nuclear protein HMGB1 modulates mitochondrial respiration by sustaining autophagy through the regulation of HSPB1. HSPB1 induce the actin filaments, which is involved in the dynamics of autophagy and mitophagy. Secreted HMGB1-RAGE complex sustains autophagy associated with decreased phosphorylation of the mTOR and increased beclin1-Ptdlns3KC3 interaction.

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