Current Understanding of HMGB1-mediated Autophagy

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 β-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.