USP-48 enables insulin-mediated longevity and modulates the mitochondrial stress response

This is the authors' abstract. We don't add key points for this paper.

The mitochondrial prohibitin (PHB) complex is essential for mitochondrial homeostasis, yet its depletion produces opposite effects on lifespan: shortening it in wild-type C. elegans but extending it in insulin/IGF-1 receptor daf-2 mutants, which show an attenuated mitochondrial unfolded protein response (UPR mt ). To identify regulators of this differential stress response and its role in aging, we conducted the first genome-wide double-RNAi screen in C. elegans . We identify the ubiquitin-specific peptidase USP-48 as a modulator of the UPR mt , specially required for lifespan extension under reduced insulin signaling. USP-48 influences mitochondrial structure and function and cooperates with the transcription factor DVE-1 to regulate the UPR mt largely independent of activating transcription factor associated with stress-1 (ATFS-1). Tissue-specific analysis shows that USP-48 is required for lifespan primarily in the hypodermis, with a smaller germline contribution, but is dispensable in muscle and intestine. Mechanistically, USP-48 promotes histone H2B deubiquitination to shape stress-responsive transcription, revealing ubiquitination as a key determinant of metabolism-dependent longevity.