117 TRANSLATION INITIATION IS ESSENTIALLY MODIFIED IN THE PORCINE ENDOMETRIAL TISSUE DURING EARLY PREGNANCY

Abstract

Protein synthesis is a major determinate in cell growth and differentiation. Here, we investigated the porcine uterine tissue during early pregnancy. The objective was the analysis of the initiation of translation, which is believed to be the rate-limiting process of protein synthesis. Performing Western blot screening during implantation and placentation, in vitro protease assays and mass spectrometry, we revealed that essential components of the cap-binding complex eIF4F and its regulators are targets of specific proteolytically processing. This proteolytical activity shifts from the implantation site to the peri-placental area later in development. The results show that the cap-binding protein eIF4E is N-terminally truncated which results in lower binding to the repressors 4E-BP1 and 4E-BP2. On the other hand, 4E-BP1 is mainly degraded, whereas 4E-BP2 emerges as N-terminally truncated stable fragments. It is likely that these fragments have lost an essential sequence motif that enables the phosphorylation and inactivation of the repressor. Furthermore, the Akt/mTor signaling cascade (which phosphorylates 4E-BP1 and 2) but not the MAPK pathway (which phosphorylated eIF4E and together with Akt/mTor hierarchically 4E-BP1 and 2) was inactivated. This results in long-term translation repression of eIF4E-sensitive and 4E-BP2-dependent mRNAs. However, other translation initiation factors like eIF4A, eIF2α, and the poly(A)-binding protein PABP are not modified. In conclusion, we suggest that the observed specific modification of the mRNA-cap-binding complex in the porcine endometrium during early pregnancy is essential to regulate gene expression to establish the noninvasive implantation and to sustain the ongoing gravidity.