title: ATF4 interacts with Abro1/KIAA0157 scaffold protein and participates in a cytoprotective pathway.
abstract: Abro1 (Abraxas brother 1), also known as KIAA0157, is a scaffold protein that recruits various polypeptides to assemble the BRISC (BRCC36 isopeptide) deubiquitinating enzyme (DUB) complex. The BRISC enzyme has a Lys63-linked deubiquitinating activity and is comprised of four known subunits: MERIT40 (mediator of Rap80 interactions and targeting 40kDa), BRE (brain and reproductive organ-expressed), BRCC36 (BRCA1/BRCA2-containing complex, subunit 3) and Abro1. We have previously shown that Abro1 has a cytoprotective role that involves the BRISC DUB complex acting on specific Lys63-linked polyubiquitinated substrates. In this report we identify three members of the AP-1 (activating protein-1) family, the ATF4, ATF5 (activating transcription factor) and JunD proteins, as specific interactors of Abro1. The function of ATF4-Abro1 interaction was investigated under normal conditions as well as under cellular stress. Abro1 is predominantly cytoplasmic, but during cellular stress it enters the nucleus and co-localizes with ATF4. Furthermore, this interaction with ATF4 is necessary and essential for the cytoprotective function of Abro1 following oxidative stress. The ability of Abro1 to specifically interact with a number of transcription factors suggests a new mechanism of regulation of the BRISC DUB complex. This regulation involves the participation of at least three known members of the AP-1 family of transcription factors.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826, USA.
authors.forename: Camilla T
authors.initials: CT
authors.lastname: Ambivero
authors.forename: Lucia
authors.initials: L
authors.lastname: Cilenti
authors.forename: Antonis S
authors.initials: AS
authors.lastname: Zervos
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D051696:Activating Transcription Factors / Q000378:metabolism*; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions; D014415:Tunicamycin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: C577338:ABRAXAS2 protein, human; C497109:ATF4 protein, human; C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D000998:Antiviral Agents; C559371:JunD protein, human; D034521:Nuclear Matrix-Associated Proteins; D016755:Proto-Oncogene Proteins c-jun; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D064570:Ubiquitin-Specific Proteases