Abstract
Small ubiquitin‐related modifier (SUMO)‐specific protease 2 (SENP2) is essential for the development of healthy placenta. The loss of SENP2 causes severe placental deficiencies and leads to embryonic death that is associated with heart and brain deformities. However, tissue‐specific disruption of SENP2 demonstrates its dispensable role in embryogenesis and the embryonic defects are secondary to placental insufficiency. SENP2 regulates SUMO1 modification of Mdm2, which controls p53 activities critical for trophoblast cell proliferation and differentiation. Here we use genetic analyses to examine the involvement of SUMO2 and SUMO3 for SENP2‐mediated placentation. The results indicate that hyper‐SUMOylation caused by SENP2 deficiency can be compensated by reducing the level of SUMO modifiers. The placental deficiencies caused by the loss of SENP2 can be alleviated by the inactivation of gene encoding SUMO2 or SUMO3. Our findings demonstrate that SENP2 genetically interacts with SUMO2 and SUMO3 pivotal for the development of three major trophoblast layers. The alleviation of placental defects in the SENP2 knockouts further leads to the proper formation of the heart structures, including atrioventricular cushion and myocardium. SUMO2 and SUMO3 modifications regulate placentation and organogenesis mediated by SENP2.
Highlights
Covalent conjugation of proteins by small ubiquitin-related modifier (SUMO) is a reversible and evolutionary conserved process.[1,2] SUMO modification can modulate a variety of cellular functions, including protein trafficking, cell cycle and cell survival/death.[3,4,5,6,7] SUMO has been shown to alter protein function, activity, interaction, andWulf Paschen: Retired in 2018.subcellular distribution
Genetic analyses described in this study clearly demonstrate that SUMO2 and SUMO3 modulate SENP2-dependent extraembryonic and embryonic development
Placental defects caused by hyper-SUMOylation in the SENP2 knockouts can be alleviated by the reduction of SUMO modifiers
Summary
Covalent conjugation of proteins by small ubiquitin-related modifier (SUMO) is a reversible and evolutionary conserved process.[1,2] SUMO modification can modulate a variety of cellular functions, including protein trafficking, cell cycle and cell survival/death.[3,4,5,6,7] SUMO has been shown to alter protein function, activity, interaction, and. The transfer of SUMO polypeptides to their targets is called “SUMOylation”, catalyzed by E3 ligases.[1,8] The reversed “deSUMOylation” process which removes SUMO is mediated by SUMO-specific proteases.[9,10] The hallmark of these proteases is a highly conserved SENP domain located at the carboxyl terminus. They catalyze deSUMOylation in various physiological systems, and genetic analysis has recently begun to unfold their importance in mammalian development and disease.[11,12,13,14,15]. The results of our genetic analysis clearly demonstrated the requirement of SUMO2 and SUMO3 for SENP2-mediated placentation that is essential for the development of the healthy embryo
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