USP18 is an essential regulator of muscle cell differentiation and maturation

USP18 is an interferon type 1 (IFN-1) induced gene that negatively regulates the IFN-1 signalling pathway, which plays a role in many immune related pathologies. Dermatomyositis (DM) is characterised by excessive IFN-1 immune response and muscle degeneration. We found USP18 to be expressed in DM myofibers suggesting a role in muscle cell biology. USP18 depletion induced muscle cell differentiation under nutrient-rich conditions independent of IFN-1 signalling. Downregulation of cell cycle gene network and sarcomeric protein networks, and dysregulation of myogenic (co-)transcription regulators were found in USP18-depleted differentiated cells. Sarcomeric integrity of USP18-depleted cells deteriorated during muscle cell maturation. Our results revealed USP18 as a critical regulator at the intersection between proliferation and differentiation as well as during the maturation of muscle cells. We suggest that a USP18 IFN-1-independent pathway may contribute to muscle regeneration in muscle pathologies. Control versus USP18 KD in nutriet-rich or starving conditions (N=4). All samples were analysed in biological triplets.