USP-48 enables insulin-mediated longevity and modulates the mitochondrial stress response
Abstract
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 (UPRmt). 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 UPRmt, 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 UPRmt 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.
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BibTeX
@article{gordillogarcia2026usp48,
title = {{USP-48 enables insulin-mediated longevity and modulates the mitochondrial stress response}},
author = {Sergio Gordillo-García and Jesus Fernandez-Abascal and Blanca Hernando-Rodríguez and María Jesús Rodríguez-Palero and Laura Cantalejo-Carrasco and Aitor Jarit-Cabanillas and Manuel D. Martínez-Bueno and Mercedes M. Pérez-Jiménez and Enrique J. Clavijo-Bernal and Aitana Cambón and Ildefonso Cases and Matthias Eder and Marta Artal-Sanz},
journal = {Cell Reports},
year = {2026},
month = sep,
doi = {10.1016/j.celrep.2026.118067},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124726011460},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - USP-48 enables insulin-mediated longevity and modulates the mitochondrial stress response
AU - Sergio Gordillo-García
AU - Jesus Fernandez-Abascal
AU - Blanca Hernando-Rodríguez
AU - María Jesús Rodríguez-Palero
AU - Laura Cantalejo-Carrasco
AU - Aitor Jarit-Cabanillas
AU - Manuel D. Martínez-Bueno
AU - Mercedes M. Pérez-Jiménez
AU - Enrique J. Clavijo-Bernal
AU - Aitana Cambón
AU - Ildefonso Cases
AU - Matthias Eder
AU - Marta Artal-Sanz
PY - 2026
DA - 2026/09/30
JO - Cell Reports
DO - 10.1016/j.celrep.2026.118067
UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124726011460
AB - 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 (UPRmt). 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 UPRmt, 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 UPRmt 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.
SN - 2211-1247
ER -