Abstract
Somatic cells age and die, but the germ-cell lineage is immortal. In Caenorhabditis elegans, germline immortality involves proteostasis renewal at the beginning of each new generation, when 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. Oocyte maturation signals are known to trigger protein-aggregate removal via lysosome acidification. Our findings suggest that lysosomes are acidified as a consequence of changes in endoplasmic reticulum activity that permit assembly of the lysosomal V-ATPase, which in turn allows lysosomes to clear the aggregates via microautophagy. We define two functions for mitochondria, both of which appear to be independent of ATP generation. 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 somatic longevity.
Highlights
The germ cells of an organism give rise to the rich diversity of somatic lineages, they generate new germ cells that, by seeding subsequent generations, confer species immortality
We find that (i) protein aggregates accumulate in young, newly formed oocytes in the absence of sperm—their formation is an integral part of oocyte development rather than a consequence of prolonged oocyte quiescence; (ii) inhibiting processes required for changes in endoplasmic reticulum (ER) morphogenesis and function during oocyte maturation, including protein synthesis and actin dynamics, prevents lysosome acidification by preventing the assembly of the V-ATPase lysosomal proton pump; (iii) mitochondria elaborate an energy-independent checkpoint that gates protein-aggregate removal; (iv) endosomal sorting complex required for transport (ESCRT) proteins are required for aggregate removal, consistent with protein aggregates being removed via microautophagy; and, unexpectedly (v) as with proteasome inhibition, inhibiting TRiC-complex chaperonins or HSP70 chaperones promotes protein aggregation indirectly by acting upstream in the pathway to block lysosome acidification
Sperm-derived signals that trigger oocyte maturation in C. elegans initiate a global change in oocyte structure and function, including the rapid removal of protein aggregates
Summary
The germ cells of an organism give rise to the rich diversity of somatic lineages, they generate new germ cells that, by seeding subsequent generations, confer species immortality This sequential rejuvenation of youthfulness is one of the most interesting mysteries in biology. In C. elegans, oocyte maturation is triggered by actin-like major sperm proteins (MSPs) released from sperm (Kosinski et al, 2005; Miller et al, 2003; Miller et al, 2001) and involves changes in chromosome and nuclear dynamics linked to progression through meiosis, upregulation of translation, and changes in endoplasmic reticulum (ER), lysosomal and mitochondrial function (Bohnert and Kenyon, 2017; Huelgas-Morales and Greenstein, 2018; Langerak et al, 2019). We show that inhibiting lysosomal V-ATPase, vesicle-transport or proteasome function accelerates age-dependent protein aggregation in the soma, bridging mechanisms that enhance proteostasis in the immortal germ lineage to those that maintain proteostasis in the aging soma
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