title: The release of high mobility group box 1 in apoptosis is triggered by nucleosomal DNA fragmentation.
abstract: High mobility group box 1 (HMGB1) initially identified as a non-histone chromosomal protein, which mainly functions as chromatin structure and transcriptional regulation, has been recently reported to be secreted into extracellular milieu in necrosis and apoptosis, and act as a proinflammatory mediator. However, the mechanism by which apoptotic cells release HMGB1 is not clear. In this study, we found that staurosporine (apoptosis-inducer)-induced HMGB1 release was associated with nucleosomal DNA fragmentation catalyzed by caspase-activated DNase (CAD) in WEHI-231 cells. Importantly, this event was effectively attenuated by the treatment of a pan-caspase inhibitor, Z-VAD-fmk, and by the inhibition of CAD-mediated DNA fragmentation by the expression of caspase-resistant inhibitor of CAD (ICAD-CR). In WEHI-231/ICAD-CR and WEHI-231/Puro cells, DNase γ-catalyzed nucleosomal DNA fragmentation occurred by anti-IgM antibody treatment was critical for HMGB1 release. Furthermore, in DNase γ stably-expressing HeLa S3 cells (HeLa S3/γ), the release of HMGB1 accompanied with nucleosomal DNA fragmentation was more apparent than that in parental HeLa S3 cells in which DNA fragmentation was scarcely observed. Taken together, these date suggest that nucleosomal DNA fragmentation catalyzed by CAD or DNase γ plays a pivotal role in HMGB1 release.
authors.affiliation: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Taku
authors.initials: T
authors.lastname: Fujii
authors.forename: Rei
authors.initials: R
authors.lastname: Ishijima
authors.forename: Haruki
authors.initials: H
authors.lastname: Tachibana
authors.forename: Natsuki
authors.initials: N
authors.lastname: Yokoue
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takasawa
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Tanuma
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D003851:Deoxyribonucleases / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; D015853:Cysteine Proteinase Inhibitors; D024243:HMGB1 Protein; D009707:Nucleosomes; D011994:Recombinant Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C109664:caspase-activated DNase inhibitor; D003851:Deoxyribonucleases; D004706:Endodeoxyribonucleases; C109663:caspase-activated deoxyribonuclease; C105124:deoxyribonuclease gamma; D020169:Caspases; D019311:Staurosporine