Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 3, Pages 1098-1110Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI76344
Keywords
-
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH through Digestive Disease Research Core Center [DK-42086, DK47722, DK097268, 1F32DK082104, P30 DK42086]
- National Institute of Allergy and Infectious Diseases (NIAID) [AI083375]
- Gastrointestinal Research Foundation
- Crohn's and Colitis Foundation of America
- Broad Medical Research Program
- Peter and Carol Goldman Family Research Fund
- Harry and Leona Helmsley Charitable Trust (SHARE)
Ask authors/readers for more resources
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 Hmgb1 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 mitigating the 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available