ATF4 interacts with Abro1/KIAA0157 scaffold protein and participates in a cytoprotective pathway

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.