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The ubiquitin-proteasome system plays a crucial role in excessive muscle proteolysis during atrophy, a condition triggered by inactivity, starvation, aging, cancer, and muscular dystrophies. While ubiquitin ligases (E3s) have been extensively studied in this process, the functions of E2 conjugating enzymes, which facilitate ubiquitin transfer with E3s, remain poorly understood. Ube2h is an E2 ubiquitin-conjugating enzyme with less understood cellular functions compared to E3 ligases. Ube2h is distinct in lacking a typical ubiquitin-binding surface and having a unique disordered C-terminal region. Our data suggest that Ube2h promotes fasting-induced muscle atrophy by impairing insulin signaling via its C-terminal region. In addition, Ube2h reduces desmin integrity by targeting the heat shock protein Hspb1 for degradation, facilitating desmin depolymerization and the resulting loss of the contractile machinery.0:0011
