title: Cleavage of the JunB transcription factor by caspases generates a carboxyl-terminal fragment that inhibits activator protein-1 transcriptional activity.
abstract: The activator protein-1 (AP-1) family transcription factor, JunB, is an important regulator of proliferation, apoptosis, differentiation, and the immune response. In this report, we show that JunB is cleaved in a caspase-dependent manner in apoptotic anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma cell lines and that ectopically expressed JunB is cleaved in murine RAW 264.7 macrophage cells treated with the NALP1b inflammasome activator, anthrax lethal toxin. In both cases, we identify aspartic acid 137 as the caspase cleavage site and demonstrate that JunB can be directly cleaved in vitro by multiple caspases at this site. Cleavage of JunB at aspartic acid 137 separates the N-terminal transactivation domain from the C-terminal DNA binding and dimerization domains, and we show that the C-terminal cleavage fragment retains both DNA binding activity and the ability to interact with AP-1 family transcription factors. Furthermore, this fragment interferes with the binding of full-length JunB to AP-1 sites and inhibits AP-1-dependent transcription. In summary, we have identified and characterized a novel mechanism of JunB post-translational modification and demonstrate that the C-terminal JunB caspase cleavage product functions as a potent inhibitor of AP-1-dependent transcription.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Alberta, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Jason K H
authors.initials: JK
authors.lastname: Lee
authors.forename: Joel D
authors.initials: JD
authors.lastname: Pearson
authors.forename: Brandon E
authors.initials: BE
authors.lastname: Maser
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ingham
mesh_terms: D000595:Amino Acid Sequence; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D019311:Staurosporine / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; C581727:JunB protein, human; C584097:JunB protein, mouse; C509168:Nalp1b protein, mouse; D010446:Peptide Fragments; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C030325:anthrax toxin; D001224:Aspartic Acid; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D020169:Caspases; D019311:Staurosporine
keywords: AP-1 Transcription Factor; Apoptosis; Caspase; Gene Transcription; Inflammasome; Jun Transcription Factor