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- Title
Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation.
- Authors
Xiaorong Zhu; Messer, Jeannette S.; Yunwei Wang; Fanfei Lin; Cham, Candace M.; Chang, Jonathan; Billiar, Timothy R.; Lotze, Michael T.; Boone, David L.; Chang, Eugene B.
- Abstract
The intracellular protein HMGB1 is released from cells and acts as a damage-associated molecular pattern molecule during many diseases, including inflammatory bowel disease (IBD); however, the intracellular function of HMGB1 during inflammation is poorly understood. Here, we demonstrated that cytosolic HMGB1 regulates apoptosis by protecting the autophagy proteins beclin 1 and ATG5 from calpain-mediated cleavage during inflammation. Colitis in mice with an intestinal epithelial cell-specific Hmgbi deletion and patients with IBD were both characterized by increased calpain activation, beclin 1 and ATG5 cleavage, and intestinal epithelial cell (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. Together, our results indicate that HMGB1 is essential for mitigatingthe extent and severity of inflammation-associated cellular injury by controlling the switch between the proautophagic and proapoptotic functions of beclin 1 and ATG5 during inflammation. Moreover, these studies demonstrate that HMGB1 is pivotal for reducing tissue injury in IBD and other complex inflammatory disorders.
- Subjects
CYTOSOL; CYTOPLASM; AUTOPHAGY; VESICLES (Cytology); APOPTOSIS
- Publication
Journal of Clinical Investigation, 2015, Vol 125, Issue 3, p1098
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI76344