A novel proteasome-ribosome axis regulated by endogenous siRNAs in oocytes governs maternal-to-zygotic transition

Small interfering RNAs (siRNAs) direct Argonaute proteins to defend against genomic invaders such as viruses and transposons. Endogenous siRNAs (endo-siRNAs) are abundantly expressed in germ cells and early embryos across diverse species; however, their physiological functions remain poorly understood. In this study, we discovered a conserved regulatory axis mediated by endo-siRNAs that involves the proteasome and ribosome, playing a crucial role in the maternal-to-zygotic transition. We demonstrate that small RNAs guide Argonaute proteins — CSR-1 in Caenorhabditis elegans and AGO2 in mice — to suppress the expression of proteasome subunits in oocytes, thereby limiting the assembly of the 26S proteasome complex. Consequently, loss of CSR-1 in worms or AGO2 in mouse oocytes results in elevated proteasome activity and accelerated degradation of ubiquitinated ribosomal proteins, leading to insufficient translation of transcription factors essential for zygotic genome activation. Notably, inhibiting proteasome activity or enhancing ribosome function can rescue early embryonic arrest caused by loss of CSR-1 or AGO2 activity. Our findings reveal a novel and conserved role of endo-siRNAs in oocytes that fine-tunes proteasome activity, ensuring degradation fidelity to help oocytes maintain the continuity of life across generations.