Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth

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Significance Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. The genetics and molecular characteristics of PTB remain unclear. FKBP51 is an important mediator of the stress response and is implicated in the etiology of stress-related disorders. By combining studies in humans and Fkbp5 −/− mice, we show that maternal stress up-regulates FKBP51 levels and enhances binding of FKBP51 to progesterone receptors. FKBP51 binding to progesterone receptors reduces progesterone receptor activity by causing functional progesterone withdrawal that induces PTB. In contrast, Fkbp5 −/− mice are resistant to maternal stress–induced PTB and exhibit prolonged gestation. These findings provide molecular insights into stress-related PTB, indicating the importance of the potential use of inhibitor(s) against FKBP51 to treat PTB in future studies.