The ubiquitin proteasomal system (UPS) is crucial for muscle physiology, and UPS impairment is implicated in many muscle pathologies. This study investigated the role of deubiquitinating enzymes (DUBs) in muscle cell differentiation. A genetic screen revealed that ubiquitin-specific protease 18 (USP18) depletion initially stimulated differentiation but later impaired myotube maintenance. Surprisingly, USP18's function in muscle cells is independent of its known role in attenuating the immune response via interferon-stimulated gene 15 (ISG15) removal. USP18 depletion altered gene expression, affecting cell cycle genes, myogenic transcription factors, and calcium channel networks. This resulted in reduced calcium flux and contractile force in engineered muscle models. Nuclear USP18 is identified as a critical regulator of both differentiation initiation and maintenance, independent of its canonical ISG15-related function.

Cyriel Sebastiaan Olie, Adán Pinto-Fernández, Andreas Damianou, Iolanda Vendrell, Hailiang Mei, Bianca den Hamer, Erik van der Wal, Jessica C. de Greef, Vered Raz, Benedikt M. Kessler