A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage

Abstract

Somatic cells age and die, but the germ-cell lineage is immortal. In C. elegans, oocyte-maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen for knockdowns that interfere with aggregate clearance. Oocyte-maturation signals are known to trigger protein-aggregate removal via lysosome acidification, and our findings suggest that lysosomes are acidified as a consequence of changes in ER morphology and function that permit assembly of the lysosomal V-ATPase. Once lysosomes are acidified, our genetic findings support the model that they remove aggregates by microautophagy. We also define two functions for mitochondria in this proteostasis renewal, both of which appear to be independent of mitochondrial ATP generation. Finally, many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and the maintenance of the soma.

Meiotic dysfunction accelerates somatic aging in Caenorhabditis elegans

“…In light of their proteostasis phenotypes, it was notable that genes downregulated in the meiotic mutants included proteostasis factors known to promote longevity including (i) rpn‐6.1 , encoding a 19S proteasome subunit that enhances lifespan in germline‐less animals (Vilchez et al, 2012) and (ii) cct‐8 and cct‐2 , chaperone‐encoding genes that modulate somatic and germline proteostasis (Noormohammadi et al, 2016; Samaddar et al, 2021; Vilchez et al, 2012). RPN‐6.1 overexpression partially rescued spo‐11 mutants' short lifespan but CCT‐2 or CCT‐8 overexpression did not (Figure 2a, Figure S3A, Table S5).…”