Fas‐associated factor 1 (FAF1) binds to mineralocorticoid Receptor (MR) through its SUMO‐interacting motifs and negatively modulates MR transcriptional activity

Abstract

Fas‐associated factor 1 (FAF1) was originally isolated as a Fas(CD95)‐associated protein factor and was subsequently found to interact with numerous other proteins that are involved in various cellular events including Fas‐mediated apoptosis, NF‐kB, Wnt/β‐catenin pathways, mineralocorticoid receptor (MR) mediated transactivation and ubiquitin‐dependent processes. Here, we define two Small Ubiquitin‐like Modifier (SUMO)‐interacting motifs (SIMs) within FAF1 and show it to be crucial for transcriptional modulation of MR. Our study demonstrated that the SIMs of FAF1 do not play a significant role in the regulation of its subcellular localization, Fas‐mediated apoptosis, NF‐kB and Wnt/β‐catenin pathways. Remarkably, FAF1 interacts sumoylated MR and represses aldosterone‐activated MR transactivation in a SIMs‐dependent manner. Moreover, silencing of endogenous FAF1 in stably MR‐expressing cells resulted in an increase in the induction of MR target genes by aldosterone, indicating that FAF1 functions as a MR corepressor. We further provide evidence to suggest that the mechanism of FAF1/SIMs‐mediated MR transrepression involves inhibition of MR N/C interaction. Sumoylation has been linked to impart repressive properties on several transcription factors and cofactors. Our findings therefore provide the mechanistic insight underlying SUMO‐dependent transcriptional repression of the MR.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.