Emerging role of SUMOylation in placental pathology

Abstract

IntroductionSmall ubiquitin-like modifiers (SUMO) conjugate to target proteins in a dynamic, reversible manner to function as post-translational modifiers. SUMOylation of target proteins can impinge on their localization, in addition to their activity or stability. Differential expression of deSUMOylating enzymes (SENP 1 and 2) contributes to altered mammalian placental development and function in mice. Severe preeclampsia (sPE) is associated with abnormal placental development and chronic ischemic injury. Extra- and intracellular stimuli/stressors that include hypoxic-activated pathways are known modulators of SUMOylation. In this current study we hypothesized that placentas from sPE patients will display up regulation in the SUMO regulatory pathway. MethodsUtilizing qRT-PCR, immuno-blotting and Western techniques, we determined the expression levels of SUMO pathway genes in healthy and diseased placentas. We also exposed placental explants to hypoxia to study the effect on the SUMOylation pathway. ResultsWe observed steady-state expression of SUMO1–3, SUMO-conjugated enzyme-UBC9 and deSUMOylating enzymes – SENPs, throughout normal gestation. An elevated level of free SUMO1–3 and SUMO-protein conjugates was observed in sPE placentas. Furthermore, placental UBC9 levels were strikingly increased in the same sPE patients. Hypoxia-induced SUMOylation in first trimester placental explants. DiscussionOur data demonstrate an elevated steady-state of SUMOylation in sPE placentas compared with gestational aged-matched controls. The observed hyper-SUMOylation in sPE placentas correlates with elevated expression of UBC9 rather than with reduced expression of SENPs Hypoxia may contribute to alterations in placental SUMOylation pathway. ConclusionIncreased placental SUMOylation may contribute to the pathogenesis of serious placental pathology that causes extreme preterm birth.