Endogenous HMGB1 regulates autophagy

Daolin Tang, et al. 2010 J. Cell Biol. 190: 881-892

Speaker：Yu-Chang Chang (張育菖)                                       Time：15:00~16:00, Dec. 1, 2010

Commentator：Dr. Chao-Yuan Tsai (蔡朝淵 博士)               Place：Room 601

Abstract:

Autophagy is a lysosomal degradation pathway that the cell self-digests its own components in response to nutrient starvation or various stresses. Autophagy serves an adaptive role to protect against infections, cancer, neurodegeneration, aging, and heart disease⁽¹⁾. Cells with metabolic or therapeutic stress release damage-associated molecule pattern molecules (DAMPs) that regulate cell death and survival. There is a prototypical DAMP called high mobility group box 1 (HMGB1) protein, which is a highly conserved chromatin-associated nuclear protein that binds to and bends DNA. HMGB1 has been shown to contribute to apoptosis⁽²⁾; however, the role of HMGB1 in autophagy remains unclear. To understand the role of HMGB1 in regulating autophagy, the authors analyzed the location of HMGB1 and found that autophagic stimuli enhanced reactive oxygen species production which promoted HMGB1 translocation from nucleus to cytosol. Mutation of cysteine 106 of HMGB1 promoted cytosolic translocation and sustained autophagy. Meanwhile, Hmgb1^-/- mouse embryonic fibroblast cytoplasts (anucleate cells) demonstrated a lower level of LC3 punctaethan Hmgb1^+/+, indicating that cytoplasmic HMGB1 was required for autophagy. Previous study showed that the phosphrylation of Bcl-2 by ERK pathway is required for its antiapoptotic effect⁽³⁾. Here they found that MEK inhibitors blocked starvation-induced phosphorylation of ERK and Bcl-2. Moreover, the oxidation of intramolecular cysteine residues Cys23 and Cys45 of HMGB1 allowed HMGB1 to directly interact with the autophagic protein Beclin 1, which disrupted Beclin 1 binding with Bcl-2 and facilitated autophagy. These findings suggest that endogenous HMGB1 plays a critical role as a pro-autophagic protein that promotes cell survival and limits apoptotic cell death.

References:

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2.          Tang D, et al. HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene. 2010 Sep 23;29(38):5299-310.

3.          Subramanian M, Shaha C. Up-regulation of Bcl-2 through ERK phosphorylation is associated with human macrophage survival in an estrogen microenvironment. J Immunol. 2007 Aug 15;179(4):2330-8.