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Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation.


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 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.

SUBMITTER: Zhu X 

PROVIDER: S-EPMC4362239 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation.

Zhu Xiaorong X   Messer Jeannette S JS   Wang Yunwei Y   Lin Fanfei F   Cham Candace M CM   Chang Jonathan J   Billiar Timothy R TR   Lotze Michael T MT   Boone David L DL   Chang Eugene B EB  

The Journal of clinical investigation 20150202 3


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 Hmg  ...[more]

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2022-09-25 | GSE161812 | GEO