The autophagy protein, ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport during early pregnancy

Abstract

AbstractRecurrent pregnancy loss (RPL), characterized by two or more failed clinical pregnancies, poses a significant challenge to reproductive health. In addition to embryo quality and endometrial function, proper oviduct function is also essential for successful pregnancy establishment. Therefore, structural abnormalities or inflammation resulting from infection in the oviduct may impede the transport of embryos to the endometrium, thereby increasing the risk of miscarriage. However, the precise cellular mechanisms that maintain the structural and functional integrity of the oviduct are not studied yet. Here, we report that autophagy is critical for maintaining the oviduct homeostasis and keeping the inflammation under check to enable embryo transport. Specifically, the loss of the autophagy-related gene,Atg14in the oviduct causes severe structural abnormalities compromising its cellular plasticity and integrity leading to the retention of embryos. Interestingly, the selective loss ofAtg14in oviduct ciliary epithelial cells did not impact female fertility, highlighting the specificity of ATG14 function in distinct cell types within the oviduct. Mechanistically, loss ofAtg14triggered unscheduled pyroptosis leading to inappropriate embryo retention and impeded embryo transport in the oviduct. Finally, pharmacological activation of pyroptosis in pregnant mice led to an impairment in embryo transport. Together, we found that ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport from the oviduct to uterus for the successful implantation. Of clinical significance, these findings provide possible insights on the underlying mechanism(s) of early pregnancy loss and might aid in developing novel prevention strategies using autophagy modulators.