title: 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.
authors: Xiaorong
authors: X
authors: Zhu
authors: Jeannette S
authors: JS
authors: Messer
authors: Yunwei
authors: Y
authors: Wang
authors: Fanfei
authors: F
authors: Lin
authors: Candace M
authors: CM
authors: Cham
authors: Jonathan
authors: J
authors: Chang
authors: Timothy R
authors: TR
authors: Billiar
authors: Michael T
authors: MT
authors: Lotze
authors: David L
authors: DL
authors: Boone
authors: Eugene B
authors: EB
authors: Chang
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002154:Calpain / Q000037:antagonists & inhibitors; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003600:Cytosol / Q000378:metabolism; D016264:Dextran Sulfate; D004151:Dipeptides / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D024243:HMGB1 Protein / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D059748:Proteolysis
chemical_list: D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D004151:Dipeptides; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008869:Microtubule-Associated Proteins; C071482:calpeptin; D016264:Dextran Sulfate; D002154:Calpain
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