TY - JOUR
T1 - An RNF12-USP26 amplification loop drives germ cell specification and is disrupted by disease-associated mutations
AU - Segarra-Fas, Anna
AU - Espejo-Serrano, Carmen
AU - Bustos, Francisco
AU - Zhou, Houjiang
AU - Wang, Feng
AU - Toth, Rachel
AU - Macartney, Thomas
AU - Bach, Ingolf
AU - Nardocci, Gino
AU - Findlay, Greg M.
N1 - Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved.
PY - 2022/7/12
Y1 - 2022/7/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85134854421&partnerID=8YFLogxK
U2 - 10.1126/scisignal.abm5995
DO - 10.1126/scisignal.abm5995
M3 - Article
C2 - 35857630
AN - SCOPUS:85134854421
SN - 1945-0877
VL - 15
JO - Science Signaling
JF - Science Signaling
IS - 742
M1 - eabm5995
ER -