Spatiotemporal distribution of small ubiquitin‐like modifiers during human placental development and in response to oxidative and inflammatory stress
Notice bibliographique
Résumé
KEY POINTS: The post-translational modification of target proteins by SUMOylation occurs in response to stressful stimuli in a variety of organ systems. Small ubiquitin-like modifier (SUMO) isoforms 1-4 have recently been identified in the human placenta, and are upregulated in the major obstetrical complication of pre-eclampsia. This is the first study to characterize the spatiotemporal distribution of SUMO isoforms and their targets during placental development across gestation and in response to stress induced by pre-eclampsia and chorioamnionitis. Keratins were identified as major targets of placental SUMOylation. The interaction with SUMOs and cytoskeletal filaments provides evidence for SUMOylation possibly contributing to underlying dysfunctional trophoblast turnover, which is a hallmark feature of pre-eclampsia. Further understanding the role of individual SUMO isoforms and SUMOylation underlying placental dysfunction may provide a target for a novel therapeutic candidate as an approach for treating pre-eclampsia complicated with placental pathology. ABSTRACT: SUMOylation is a dynamic, reversible post-translational modification that regulates cellular protein stability and localization. SUMOylation occurs in response to various stressors, including hypoxia and inflammation, features common in the obstetrical condition of pre-eclampsia. SUMO isoforms 1-4 have recently been identified in the human placenta, but less is known about their role in response to pre-eclamptic stress. We hypothesized that SUMOylation components have a unique spatiotemporal distribution during placental development and that their subcellular localization can be further modulated by extra-cellular stressors. Placental SUMO expression was examined across gestation. First-trimester human placental explants and JAR cells were subjected to hypoxia or TNF-α cytokine, and subcellular translocation of SUMOs was monitored. SUMOylation target proteins were elucidated using mass spectrometry and proximity ligation assay. Placental SUMO-1 and SUMO-4 were restricted to villous cytotrophoblast cells in first trimester and syncytium by term, while SUMO-2/3 staining was evenly distributed throughout the trophoblast across gestation. In placental villous explants, oxidative stress induced hyperSUMOylation of SUMO-1 and SUMO-4 in the syncytial cytoplasm, whereas SUMO-2/3 nuclear expression increased. Oxidative stress also upregulated cytoplasmic SUMO-1 and SUMO-4 protein expression (P < 0.05), similar to pre-eclamptic placentas. Keratins were identified as major targets of placental SUMOylation. Oxidative stress increased the cytokeratin-7 to SUMO-1 and SUMO-4 interactions, while inflammatory stress increased its interaction with SUMO-2/3. Overall, SUMOs display a unique spatiotemporal distribution in normal human placental development. Our data indicate SUMOylation in pre-eclampsia, which may impair the stability of cytoskeleton filaments and thus promote trophoblast shedding into the maternal circulation in this condition.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».