1. Ubiquitin-proteasome systems in muscle homeostasis.
Ubiquitin-proteasome systems in muscle homeostasis. E1 enzymes activate ubiquitin proteins after the cleavage of ATP. The ubiquitin is then moved from E1 to members of the E2 enzyme class. The final ubiquitylation reaction is catalyzed by members of the E3 enzyme class. E3 binds to E2 and the protein substrate, inducing the transfer of ubiquitin from E2 to the substrate. Once the substrate is polyubiquitylated, it is docked to the proteasome for degradation. Note that polyubiquitin chains can be removed by de-ubiquitylating enzymes [ubiquitin-specific processing proteases (USPs)]. The components of this system that contribute to muscle wasting are depicted. ZNF216 is involved in the recognition and delivery to the proteasome of ubiquitylated proteins during muscle atrophy. Atrogin-1 regulates the half-life of the MyoD transcription factor and of eIF3f, which is crucial for protein synthesis. Fbxo40 regulates the half-life of IRS1, an essential factor for IGF1/insulin signaling, whereas MuRF1 regulates the half-life of several sarcomeric proteins. E3 ubiquitin ligases are depicted in green, with arrows pointing to their substrates. Note that ubiquitin ligases can have different cellular localizations and can shuttle into the nucleus. IRS1, insulin receptor substrate 1; Ub, ubiquitin.
Paolo Bonaldo, and Marco Sandri Dis. Model. Mech. 2013;6:25-39
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