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PMID: 25642769 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 125 ·No. 3 ·2015-03-02 ·Pages 1098-110

Zhu X, Messer JS, Wang Y, Lin F, Cham CM, Chang J, Billiar TR, Lotze MT, Boone DL, Chang EB

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.

MeSH Terms
Adaptive Immunity Animals Apoptosis Apoptosis Regulatory Proteins/metabolism Autophagy Autophagy-Related Protein 5 Beclin-1 Calpain/antagonists & inhibitors Cell Cycle Checkpoints Cells, Cultured Colitis/chemically induced,metabolism,pathology Cytosol/metabolism Dextran Sulfate Dipeptides/pharmacology Epithelial Cells/physiology Female HMGB1 Protein/physiology Humans Intestinal Mucosa/pathology Male Mice, Inbred C57BL Mice, Transgenic Microtubule-Associated Proteins/metabolism Proteolysis
Chemicals
Apoptosis Regulatory Proteins Atg5 protein, mouse Autophagy-Related Protein 5 Beclin-1 Becn1 protein, mouse Dipeptides HMGB1 Protein HMGB1 protein, mouse Microtubule-Associated Proteins calpeptin Dextran Sulfate Calpain
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Zhu Xiaorong
Messer Jeannette S
Wang Yunwei
Lin Fanfei
Cham Candace M
Chang Jonathan
Billiar Timothy R
Lotze Michael T
Boone David L
Chang Eugene B
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI76344
Published
2015-03-02
Epub
2015-00-02
Pages
1098-110
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC4362239
Subset
IM
Grants
NIDDK NIH HHS · P30 DK042086 · United States
NIDDK NIH HHS · 1F32DK082104 · United States
NIDDK NIH HHS · DK-42086 · United States
NIAID NIH HHS · R01 AI083375 · United States
NIDDK NIH HHS · R37 DK047722 · United States
NIAID NIH HHS · T32 AI007090 · United States
NIDDK NIH HHS · F32 DK082104 · United States
NIAID NIH HHS · AI083375 · United States
NIDDK NIH HHS · DK097268 · United States
NIDDK NIH HHS · DK47722 · United States
NIDDK NIH HHS · R01 DK097268 · United States
NIDDK NIH HHS · P30 DK42086 · United States
NIDDK NIH HHS · R01 DK047722 · United States
External Links
PubMed source DOI: 10.1172/JCI76344 PMC Full Text View journal details
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