An RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations

Anna Segarra-Fas, Carmen Espejo-Serrano, Francisco Bustos, Houjiang Zhou, Feng Wang, Rachel Toth, Thomas Macartney, Ingolf Bach, Gino Nardocci, Greg M. Findlay

Research output: Contribution to journalArticlepeer-review

Abstract

The E3 ubiquitin ligase RNF12 plays essential roles during development, and the gene encoding it, RLIM, 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 Usp26, 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-dependent derepression of REX1 targets. We showed that the RNF12-USP26 axis operated specifically in mouse testes and was required for the expression of gametogenesis genes and for germ cell differentiation in vitro. Furthermore, this RNF12-USP26 axis was disrupted by RLIM and USP26 variants found in TOKAS and infertility patients, respectively. This work reveals synergy within the ubiquitylation cycle that controls a key developmental process in gametogenesis and that is disrupted in human genetic disorders.

Original languageEnglish
Pages (from-to)eabm5995
JournalScience Signaling
Volume15
Issue number742
DOIs
StatePublished - 12 Jul 2022

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