Stella safeguards proteostasis via regulating UBE2D3 translation in the maternal-to-zygotic transition

Ubiquitin-proteasome-mediated protein degradation is essential for maternal-to-zygotic transition, yet the maternal factors that safeguard ubiquitin-proteasome function remain unclear. Here, using a Stella loss-of-function mouse model, we demonstrate that Stella is required for global protein ubiquitination during early embryogenesis. Stella deficiency in oocytes leads to reduced ubiquitinated protein levels, impaired zygotic genome activation, and early developmental arrest. Proteomic and functional analysis identify UBE2D3 as the key E2 enzyme whose insufficiency underlies the ubiquitination defect. Mechanistically, Stella preserves YBX3 stability, thereby enabling YBX3-dependent translation of Ube2d3 mRNA. Consequently, Stella depletion destabilizes YBX3, diminishes UBE2D3 synthesis, and disrupts protein ubiquitination. Notably, overexpression of Ybx3 or Ube2d3 partially restores ubiquitinated protein levels, zygotic genome activation, and embryo development. These findings identify a previously unrecognized Stella-YBX3-UBE2D3 axis that ensures efficient maternal protein ubiquitination and zygotic genome activation, revealing a cytoplasmic mechanism by which maternal Stella governs proteostasis during maternal-to-zygotic transition.