The autophagosome delivers damaged cytoplasmic constituents and proteins to the lysosome or to the extracellular space. Beclin 1, an essential
autophagic protein, is a BH3-only protein that binds Bcl-2 anti-apoptotic family members and has a critical role in the initiation of autophagy. How the Beclin 1 complex specifically promotes autophagy remains largely unknown. We have found that high mobility group box 1 (HMGB1), a chromatin-associated nuclear protein and extracellular damage associated molecular pattern molecule (DAMP), is a novel Beclin 1-binding protein important in sustaining autophagy. HMGB1 shares considerable sequence homology with Beclin 1 in yeast, mice and human, representing an evolutionarily conserved regulatory step in early autophagosome formation. Endogenous HMGB1 competes with Bcl-2 for interaction with Beclin 1, and orients Beclin 1 to autophagosomes. Moreover, the intramolecular disulfide bridge (C23/45) of HMGB1 is required for binding to Beclin 1 and sustaining autophagy. Taken together, these findings indicate that endogenous HMGB1 functions as an autophagy effector by regulation of autophagosome formation.
D Tang, R Kang, KM Livesey, CW Cheh, A Farkas, P Loughran, G Hoppe, ME Bianchi, KJ Tracey, HJ 3rd Zeh, MT Lotze. Endogenous HMGB1 regulates autophagy. J Cell Biol 2010; 190: 881- 92.
PMID: 20819940 DOI: 10.1083/jcb.20091107