USP24 is a cross-reactive DUB targeting MOV10 to regulate IFN-I production
11 affiliations
- 1Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
- 2Centre for Medicines Discovery, University of Oxford, Oxford, UK
- 3Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK
- 4Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
- 5Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
- 6Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- 7Institute of Neuropathology, University of Freiburg, Freiburg, Germany
- 8Department of Cellular Microbiology, University of Hohenheim, Stuttgart, Germany
- 9Department of Molecular and Cell Biology, National Center for Biotechnology (CNB-CSIC), Madrid, Spain
- 10Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. [email protected]
- 11Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. [email protected]
Abstract
The type I Interferon (IFN-I)-induced ubiquitin-like modifier Interferon-Stimulated Gene 15 (ISG15) plays a crucial role in the innate immune response against viral infections. ISG15 is conjugated to target proteins by an enzymatic cascade, called ISGylation. While ubiquitin-specific protease 18 (USP18) serves as the major deISGylase counteracting ISG15 conjugation, ISG15 cross-reactive deubiquitylating enzymes (DUBs) have also been reported. Here, we identify USP24 as an ISG15 cross-reactive DUB through activity-based protein profiling. USP24 processes pro-ISG15 and ISG15-linked substrates in vitro, and its depletion increases ISG15 conjugates following interferon stimulation in cells without altering canonical IFN-I signaling. USP24 knockout cells show increased IFN-β and ISG expression upon activation of cytosolic RNA sensing via viral mimicry. Proteomic analysis identifies RNA helicase Moloney leukemia virus 10 (MOV10) as a specific target of USP24 for deISGylation. Our data revealed that ISGylation of MOV10 promotes MOV10 interaction with IFIT3 and enhances IFN-β production/secretion in response to viral stimuli. This process is negatively regulated by USP24, which directly deISGylates MOV10. Our data highlight USP24's role in modulating ISGylation and IFN-I production, suggesting USP24 as a potential therapeutic agent for infectious and inflammatory diseases.
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BibTeX
@article{mukhopadhyay2026usp24,
title = {{USP24 is a cross-reactive DUB targeting MOV10 to regulate IFN-I production}},
author = {Rishov Mukhopadhyay and Simeon D. Draganov and Timo Oosenbrug and Jimmy J.L.L. Akkermans and Marjolein Kikkert and Klaus‐Peter Knobeloch and Günter Fritz and M Ángeles Guzmán and Sonia Zúñiga and Robbert Q. Kim and Annemarthe G. van der Veen and Benedikt Mathias Kessler and Adán Pinto-Fernández and Paul P. Geurink and Ayşegül Sapmaz},
journal = {Nature Communications},
year = {2026},
month = jun,
doi = {10.1038/s41467-026-74490-2},
url = {https://doi.org/10.1038/s41467-026-74490-2},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - USP24 is a cross-reactive DUB targeting MOV10 to regulate IFN-I production
AU - Rishov Mukhopadhyay
AU - Simeon D. Draganov
AU - Timo Oosenbrug
AU - Jimmy J.L.L. Akkermans
AU - Marjolein Kikkert
AU - Klaus‐Peter Knobeloch
AU - Günter Fritz
AU - M Ángeles Guzmán
AU - Sonia Zúñiga
AU - Robbert Q. Kim
AU - Annemarthe G. van der Veen
AU - Benedikt Mathias Kessler
AU - Adán Pinto-Fernández
AU - Paul P. Geurink
AU - Ayşegül Sapmaz
PY - 2026
DA - 2026/06/19
JO - Nature Communications
DO - 10.1038/s41467-026-74490-2
UR - https://doi.org/10.1038/s41467-026-74490-2
AB - The type I Interferon (IFN-I)-induced ubiquitin-like modifier Interferon-Stimulated Gene 15 (ISG15) plays a crucial role in the innate immune response against viral infections. ISG15 is conjugated to target proteins by an enzymatic cascade, called ISGylation. While ubiquitin-specific protease 18 (USP18) serves as the major deISGylase counteracting ISG15 conjugation, ISG15 cross-reactive deubiquitylating enzymes (DUBs) have also been reported. Here, we identify USP24 as an ISG15 cross-reactive DUB through activity-based protein profiling. USP24 processes pro-ISG15 and ISG15-linked substrates in vitro, and its depletion increases ISG15 conjugates following interferon stimulation in cells without altering canonical IFN-I signaling. USP24 knockout cells show increased IFN-β and ISG expression upon activation of cytosolic RNA sensing via viral mimicry. Proteomic analysis identifies RNA helicase Moloney leukemia virus 10 (MOV10) as a specific target of USP24 for deISGylation. Our data revealed that ISGylation of MOV10 promotes MOV10 interaction with IFIT3 and enhances IFN-β production/secretion in response to viral stimuli. This process is negatively regulated by USP24, which directly deISGylates MOV10. Our data highlight USP24's role in modulating ISGylation and IFN-I production, suggesting USP24 as a potential therapeutic agent for infectious and inflammatory diseases.
SN - 2041-1723
ER -