biostudies-literatureSegarra-Fas AMedical Research CouncilWellcome TrustNIGMS NIH HHSeabm5995https://www.ebi.ac.uk/biostudies/studies/S-EPMC7613676biostudies-literatureUnknown15(742)The E3 ubiquitin ligase RNF12 plays essential roles during development, and the gene encoding it, <i>RLIM</i>, is mutated in the X-linked human developmental disorder Tonne-Kalscheuer syndrome (TOKAS). Substrates of RNF12 include transcriptional regulators such as the pluripotency-associated transcriptional repressor REX1. Using global quantitative proteomics in male mouse embryonic stem cells, we identified the deubiquitylase USP26 as a putative downstream target of RNF12 activity. RNF12 relieved REX1-mediated repression of <i>Usp26</i>, leading to an increase in USP26 abundance and the formation of RNF12-USP26 complexes. Interaction with USP26 prevented RNF12 autoubiquitylation and proteasomal degradation, thereby establishing a transcriptional feed-forward loop that amplified RNF12-depeScience signalingAn RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations.PMC7613676211209MR/N000609/1211209/Z/18/ZR01 GM128168Espejo-Serrano CBustos FSegarra-Fas AToth RBach IWang FNardocci GFindlay GMZhou HMacartney TfalseAn RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations.The E3 ubiquitin ligase RNF12 plays essential roles during development, and the gene encoding it, <i>RLIM</i>, is mutated in the X-linked human developmental disorder Tonne-Kalscheuer syndrome (TOKAS). Substrates of RNF12 include transcriptional regulators such as the pluripotency-associated transcriptional repressor REX1. Using global quantitative proteomics in male mouse embryonic stem cells, we identified the deubiquitylase USP26 as a putative downstream target of RNF12 activity. RNF12 relieved REX1-mediated repression of <i>Usp26</i>, leading to an increase in USP26 abundance and the formation of RNF12-USP26 complexes. Interaction with USP26 prevented RNF12 autoubiquitylation and proteasomal degradation, thereby establishing a transcriptional feed-forward loop that amplified RNF12-depe2022-01-01T00:00:00Z2022 Jul2026-07-14T16:07:59.871Z2024-10-18T02:25:23.994ZS-EPMC76136763585763010.1126/scisignal.abm5995