USP24 is a cross-reactive DUB targeting MOV10 to regulate IFN-I production

Year: 2026

Type: article

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.

Source: Nature Communications

DOI: 10.1038/s41467-026-74490-2

Authors: Rishov Mukhopadhyay, Simeon D. Draganov, Timo Oosenbrug, Jimmy J. L. L. Akkermans, Marjolein Kikkert, Klaus-Peter Knobeloch, Günter Fritz, María Guzmán, Sonia Zuñiga, Robbert Q. Kim, Annemarthe G. van der Veen, Benedikt M. Kessler, Adán Pinto-Fernández, Paul P. Geurink, Aysegul Sapmaz

Institutions: Leiden University Medical Center, University of Oxford, University of Freiburg, University of Hohenheim, Consejo Superior de Investigaciones Científicas, Centro Nacional de Biotecnología

Language: English

Topic: interferon and immune responses

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,990

Funders: Pfizer, University of Miami, Comunidad de Madrid, European Commission, Deutsche Forschungsgemeinschaft, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Leids Universitair Medisch Centrum, Chinese Academy of Medical Sciences, Agencia Estatal de Investigación

OpenAlex ID: W7165127349