Abstract
Degradation of maternal proteins by the ubiquitin-proteasome system (UPS) accompanies the maternal-to-zygotic transition. DPPA3/Stella/PGC7, encoded by a maternal effect gene, is present in the nucleus and cytoplasm of zygotes and has been associated with protecting the female pronucleus from TET3-mediated demethylation. We now report that cytoplasmic DPPA3 is partially cleaved by the ubiquitin-proteasome system and an N-terminus fragment remains in the cytoplasm where it associates with early and re-cycling endosomes. If DPPA3 is absent or if cleavage is prevented, multiple vesicles coalesce/aggregate and markers of lysosomes are decreased. Fertilized eggs develop poorly into blastocysts, which results in significantly decreased fecundity of Dppa3R60A transgenic mice. This phenocopies aspects of Lamp1/2 knockdowns and Dppa3KO embryos can be partially rescued in vitro by DPPA31–60 and to a lesser extent by LAMP1/2. Thus, the N-terminus of DPPA3 has a significant role in cytoplasmic vesicular trafficking in addition to its previously reported nuclear function.
Highlights
Degradation of maternal proteins by the ubiquitin-proteasome system (UPS) accompanies the maternal-to-zygotic transition
Several partially cleaved maternal proteins were detected and we focused on DPPA3, which is essential for normal mouse pre-implantation development
After treatment with MG132 to inhibit proteasomal degradation, DPPA3WT-monomer Venus (mVenus) was observed adjacent to the plasma membrane in 1C zygotes (Supplementary Fig. 2h), and no cleavage of DPPA3K96A was detected by immunoblot in transiently transfected cells (Supplementary Fig. 2i). These results indicate that cleavage of DPPA3 at 59LR↓NR62 is required for retention in the cytoplasm and that the subsequent degradation is mediated by ubiquitination of Lys[96] and the UPS
Summary
Degradation of maternal proteins by the ubiquitin-proteasome system (UPS) accompanies the maternal-to-zygotic transition. Maternal effect genes encode proteins that accumulate during oogenesis and are essential for cleavage-stage embryonic development. Many of these same proteins undergo proteolytic processing by the ubiquitin-proteasome system (UPS) in the early embryo. When degradation of maternal proteins is prevented by ablation of proteasome subunits, embryonic development is arrested or significantly delayed in early cleavage stages without affecting oogenesis[11,12]. These observations raise the possibility that cleavage by the UPS after fertilization may activate maternal proteins necessary for the reprograming oocytes into totipotent zygotes. The absence of the DPPA3 cleavage products adversely affects pre-implantation development and female fertility
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