USP-48 modulates mitochondrial stress and enables longevity in low-insulin worms

In Caenorhabditis elegans, depletion of the mitochondrial prohibitin complex shortens life in wild-type animals but extends it in long-lived daf-2 mutants. To find regulators of this divergence, researchers conducted a genome-wide double-RNAi screen. They discovered that the deubiquitinating enzyme USP-48 is required for lifespan extension under reduced insulin signaling. USP-48 affects mitochondrial structure and function and helps regulate the mitochondrial unfolded protein response alongside the transcription factor DVE-1, acting largely independent of ATFS-1. Tissue-specific experiments revealed that USP-48 functions primarily in the hypodermis, with some contribution from the germline, while remaining dispensable in muscle and intestine. Mechanistically, USP-48 promotes histone H2B deubiquitination to alter stress-responsive gene transcription.