Evolutionary Conserved Regulation of TFEB Stability by the E3 Ubiquitin Ligase WWP2 Modulates Response to Stress

Overview

Journal iScience

Publisher Cell Press

Date 2025 Feb 25

PMID 39995862

Authors

Juan A Garcia-Sanchez

Estelle Bonnet

Celine Loubatier

Anne Doye

Guillaume Paillier

Fabien Segui

Frederic Larbret

Paul Chaintreuil

Ludovic Batistic

Cedric Torre

Marcel Deckert

Jolanta Polanowska

Patrick Munro

Laurent Boyer

Orane Visvikis

Affiliations

Soon will be listed here.

Abstract

Transcription factor EB (TFEB) is a key transcription factor that orchestrates the cellular response to stress. Dysregulation of TFEB is associated with a range of human diseases, and understanding the regulatory mechanisms of TFEB is crucial for identifying potential drug targets. In this study, we used to screen for E3 ubiquitin ligases regulating the activity of TFEB's homolog, HLH-30, upon pathogenic infection. We identified WWP-1 as a regulator of HLH-30-dependent immune response controlling HLH-30 stability to mediate host defense . We found that HLH-30 interacts with WWP-1, supporting a model of WWP-1 directly regulating HLH-30. Furthermore, we found that WWP-1's human homolog WWP2 binds TFEB, directly induces TFEB ubiquitination and stabilizes TFEB. Finally, we found that WWP2 is required for TFEB-dependent host response in human monocytes-derived macrophages upon infection. Overall, our work has identified an evolutionarily conserved regulation of TFEB by WWP2 and highlighted its role in modulating stress response.

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