Mouse oocytes sequester aggregated proteins in degradative super-organelles

Oocytes are among the longest-lived cells in the body and need to preserve their cytoplasm to support proper embryonic development. Protein aggregation is a major threat for intracellular homeostasis in long-lived cells. How oocytes cope with protein aggregation during their extended life is unknown. Here, we find that mouse oocytes accumulate protein aggregates in specialized compartments that we named endolysosomal vesicular assemblies (ELVAs). Combining live-cell imaging, electron microscopy, and proteomics, we found that ELVAs are non-membrane-bound compartments composed of endolysosomes, autophagosomes, and proteasomes held together by a protein matrix formed by RUFY1. Functional assays revealed that in immature oocytes, ELVAs sequester aggregated proteins, including TDP-43, and degrade them upon oocyte maturation. Inhibiting degradative activity in ELVAs leads to the accumulation of protein aggregates in the embryo and is detrimental for embryo survival. Thus, ELVAs represent a strategy to safeguard protein homeostasis in long-lived cells. [Display omitted] •Mouse oocytes store protein aggregates in endolysosomal vesicular assemblies (ELVAs)•ELVAs harbor endolysosomes, autophagosomes, and proteasomes in a liquid-like matrix•ELVAs degrade aggregates upon oocyte maturation to promote healthy embryogenesis•Retention of protein aggregates in the embryo leads to early embryonic arrest Mouse oocytes store protein aggregates in liquid-like compartments that we named endolysosomal vesicular assemblies (ELVAs) in which the aggregates are degraded upon oocyte maturation. Failure to degrade aggregates in ELVAs causes early embryonic arrest.