Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation

 J Clin Invest. 2015; 125(3):1098-110

Speaker: Yu-Lun, Chen (陳昱倫)                                         Time: 14:00~15:00, Mar. 2, 2016

Commentator: Dr. Chih-Peng, Chang (張志鵬 老師)         Place: Room 601

Abstract:

       High mobility group box 1 (HMGB1) is a nuclear non-histone DNA-binding protein. The extracellular HMGB1 is recently discovered to be a crucial cytokine that mediates the response to infection, injury and inflammation disease, including inflammatory bowel disease (IBD).(Yamasaki et al., 2009) However, the intracellular function of HMGB1 during IBD is poorly understood. To study the intracellular role of HMGB1 in intestinal epithelial cell (IEC) during colitis, authors created an mice model lacking Hmgb1 solely in IECs and treated these mice with DSS to induce colitis. Their findings showed that cytosolic HMGB1 regulates apoptosis by protecting the autophagy proteins beclin 1 and ATG5 from calpain-mediated cleavage during colitis. Colitis in mice with an intestinal epithelial cell–specific Hmgb1 deletion and patients with IBD were both characterized by increased calpain activation, beclin 1 and ATG5 cleavage and IEC death compared with controls. In vitro cleavage assays and studies of enteroids verified that HMGB1 protects beclin 1 and ATG5 from calpain-mediated cleavage events that generate proapoptotic protein fragments. Take together,these results indicate that HMGB1 is essential for mitigating the severity of inflammation-associated cellular injury by controlling the switch between the proautophagic and proapoptotic functions of beclin 1 and ATG5 during inflammation. Moreover, this study demonstrate that HMGB1 plays an important role for reducing tissue injury in IBD and other complex inflammatory disorders. As such, it may represent a useful therapeutic target in inflammatory disease.

Reference:

1.  Yamasaki, H., Mitsuyama, K., Masuda, J., Kuwaki, K., Takedatsu, H., Sugiyama, G., Yamada, S., and Sata, M. (2009). Roles of high-mobility group box 1 in murine experimental colitis. Molecular medicine reports 2, 23-27.