A lysosomal surveillance response (LySR) that reduces proteotoxicity and extends healthspan

SUMMARY Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the Lysosomal Surveillance Response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H + -ATPase subunits in Caenorhabditis elegans . Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimer’s and Huntington’s disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan. The GATA transcription factor, ELT-2, regulates the LySR program as well as its associated beneficial effects. In mammalian cells, overexpression of GATA4/GATA6, the mammalian orthologs of ELT-2, is sufficient to induce the expression of multiple lysosome-specific proteases and alleviate proteotoxicity. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan. Highlights RNAi of specific v-ATPase subunits extends C. elegans lifespan and activates LySR GATA transcription factor ELT-2 regulates LySR and LySR-associated lifespan extension LySR activation reduces protein aggregates and extends worm healthspan Overexpression of GATA4/GATA6 alleviates amyloid-β proteotoxicity in mammalian cells