USP18 is an essential regulator of muscle cell differentiation and maturation

Highlights USP18 knockdown results in transcriptome-wide changes that cause a switch from proliferation to muscle cell differentiation. Fully differentiated muscles cells (or simply 'myotubes') formed in absence of USP18 lack sarcomeric integrity (in both cell culture and engineered muscle models). An increase in USP18 expression during muscle cell differentiation is independent of its role in the interferon type 1 stimulated response. During normal muscle cell differentiation, USP18 accumulates in the cell nucleus regulating multiple cellular processes, including proliferation, differentiation initiation and muscle cell maturation. In the absence of USP18, muscle cells stop proliferating and undergo accelerated fusion as part of the differentiation process by altering the expression levels of myogenic regulatory (co-)transcription factors, whereas maturation is impaired due to reduced expression of calcium-flux genes and sarcomeric genes.