The survival of any animal species relies on the continuity of its germ cell lineage. How germ cells avoid transmitting damage from one generation to the next remains a fundamental, unsolved question in biology. Here, we identify a sperm-triggered lysosomal switch that improves oocyte proteostasis just prior to fertilization. We find that sperm-secreted hormones activate a signaling cascade that eliminates multiple types of protein aggregates from Caenorhabditis elegans oocytes. A key step in this cascade is the acidification of lysosomes, a process driven by the vacuolar ATPase (V-ATPase). Our findings indicate that sperm signaling triggers lysosome acidification by abolishing GLD-1-mediated translational repression of V-ATPase RNAs. The lysosomal acidity established upon V-ATPase synthesis, in turn, affects protein aggregation by promoting mitochondrial homeostasis. Given that we likewise observe lysosome acidification during Xenopus oocyte maturation, we propose that this event clears cellular damage and enhances oocyte health in anticipation of fertilization in multiple species. Taken together, these findings highlight a lysosome-based quality control switch that may contribute to the trans-generational maintenance of an immortal germ lineage. We are now exploring whether a similar lysosomal switch can be artificially induced in the somatic tissues of aged worms to erase markers of aging and improve healthspan. .
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