USP18 is an essential regulator of muscle cell differentiation and maturation

Abstract

Muscle degeneration, a key feature in a wide range of human pathologies, is typified by impaired proteastasis, in which the ubiquitin proteasomal system in particular plays an important role. Yet, little is known about the function of deubiquitinating enzymes (DUBs) in muscle cell biology. We performed a genetic screen to identify DUBs regulators of muscle cell differentiation. Surprisingly, we observed that USP18-depletion induced differentiation and reduced proliferation of muscle cells. USP18 enzymatic function typically attenuates the immune response by removing ISG15, but in muscle cells, we found that USP18 regulates differentiation independent of ISG15 and the IFN-1 pathway. USP18 accumulation in muscle cell nuclei was concomitant with reduced expression of the cell-cycle gene network and altered transcription-regulated gene networks, including myogenic transcription factors. Additionally, USP18-depletion altered calcium channel gene networks, which was in line with reduced calcium flux in myotubes. Reduced sarcomeric genes were linked to reduced contractile force in an engineered muscle model. Our results revealed nuclear USP18 as a critical regulator of differentiation initiation and differentiation maintenance, independent of the IFN-1 pathway.

Unravelling the Transcriptomic Symphony of Sarcopenia: Key Pathways and Hub Genes Altered by Muscle Ageing and Caloric Restriction Revealed by RNA Sequencing

“…These functions possibly contribute to its effects on muscle loss. Ifit3 (Interferon-induced protein with tetratricopeptide repeats 3) and Usp18 (Ubiquitin-specific protease 18) are also involved in interferon-mediated immune responses. Their dysregulation with ageing may contribute to chronic inflammation phenotypes 51,52 . Usp18 is also a known regulator of muscle cell differentiation 52 . Rsad2 (Radical S-adenosyl methionine domain-containing protein 2) plays a role in defence against viruses.…”

“…Their dysregulation with ageing may contribute to chronic inflammation phenotypes 51,52 . Usp18 is also a known regulator of muscle cell differentiation 52 . Rsad2 (Radical S-adenosyl methionine domain-containing protein 2) plays a role in defence against viruses. Its involvement in muscle ageing likely relates to its ability to modulate cellular responses to stress, as has been shown in age-related macular degeneration 53,54 Furthermore, Bid and B2m also appeared to be involved both in ageing and in responses to CR.…”

“…Ifit3 (Interferon-induced protein with tetratricopeptide repeats 3) and Usp18 (Ubiquitin-specific protease 18) are also involved in interferon-mediated immune responses. Their dysregulation with ageing may contribute to chronic inflammation phenotypes 51,52 . Usp18 is also a known regulator of muscle cell differentiation 52 .…”

“…Their dysregulation with ageing may contribute to chronic inflammation phenotypes 51,52 . Usp18 is also a known regulator of muscle cell differentiation 52 .…”

Proximity proteomics reveals UCH-L1 as an NLRP3 interactor that modulates IL-1β production in human macrophages and microglia

“…Fragment ion spectra (MS/MS) were obtained in the Ion trap (rapid scan mode) with a Quad isolation window of 1.6, 40% AGC target and a maximum injection time of 35 ms, with HCD activation and 28% collision energy. Raw MS files were analysed using MaxQuant software (v1.6.10.43) using label free quantitation (LFQ) as described previously (Olie et al, 2023). In brief, raw MS files were searched against the UniProtKB human sequence database (UP000005640, 79,038 human sequence entries).…”