Circ-0081343 binds and activates RBM8A nuclear translocation to promote autophagy in Fetal growth restriction

Abstract

Abstract Fetal growth restriction (FGR) is a common disease that occurred during pregnancy and is the second leading cause of perinatal death, affecting neonates' short- and long-term prognosis. However, the etiology and pathogenesis of FGR are poorly understood. Recent study found that circ-0081343 is significantly reduced in human FGR placenta and is involved in cell migration, invasion, and apoptosis of trophoblast in vitro. However, the mechanism of how circ-0081343 regulates placental development have not been fully understood. In this study, we aimed to explore the function of circ-0081343 in pathogenesis of FGR placenta using in vitro experiment and FGR mouse model. Overexpression of circ-0081343 in HTR-8/SVneo increased the binding of circ-0081343 to RNA binding motif protein 8A (RMB8A). Furthermore, it also inhibited the nuclear translocation of RMB8A via downregulating the importin 13 (IPO13), which transported RMB8A across the nuclear membrane into the nucleus. Based on the integration of RNA-seq and Chip-seq, we found that phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) pathway was the target of circ-0081343. circ-0081343 bound to RMB8A and inhibited its nuclear translocation, resulting in inactivation of PI3K/AKT pathway via interaction with PI3K3C3, thereby regulating autophagy in HTR-8/SVneo cells. In FGR mouse model, overexpression of circ-0081343 was able to restore the impaired autophagy through inhibition of PI3K/AKT pathway, improving pathological placenta and bodyweight of pups. These results provided new molecular targets and ideas for the diagnosis and treatment of clinical FGR from the perspective of circRNA affecting the nuclear translocation of binding proteins and leading to abnormal transcriptional control.