Interactions Between E3 Ubiquitin Ligases and Deubiquitinases in AKT Regulation: Implications in Skeletal Muscle Homeostasis.

AKT (protein kinase B, PKB) coordinates the balance between anabolic and catabolic signaling in skeletal muscle through distinct ubiquitin chain types. Some E3 ubiquitin ligases (E3s) and deubiquitinases (DUBs) form stable binary complexes via non-catalytic interfaces, adding a regulatory layer unavailable to either enzyme alone. This mechanistic synthesis review presents a systematic literature analysis (inception to May 2026; 26 eligible studies). It identified four E3-DUB pairs proposed to regulate AKT in skeletal muscle. These are TRAF6-CYLD (plasma-membrane K63-ubiquitination), MUL1-USP9X (mitochondrial K48-ubiquitination of AKT2), CHIP-UCH37 (proteasome-proximal quality control), and SCF-Skp2-USP37 (PHLPP1/2-dependent control of AKT Ser473 phosphorylation). All four interfaces are structurally separate from the catalytic sites and are regulated by upstream kinase phosphorylation. Evidence for the four pairs is markedly uneven. TRAF6-CYLD is supported by endogenous co-immunoprecipitation and functional data in muscle models. CHIP and UCH37 each act on AKT-related substrates independently and are individually well documented, but a direct CHIP-UCH37 interaction has not itself been demonstrated. SCF-Skp2-USP37 interaction data rest on a real but non-muscle direct interaction, whereas MUL1-USP9X has no reported direct interaction at all; CHIP-UCH37, SCF-Skp2-USP37, and MUL1-USP9X are therefore all presented as testable hypotheses of varying strength. In chronic atrophy, available data are consistent with disruption of these complexes contributing to AKT suppression through parallel, largely independent mechanisms. However, simultaneous disruption of all four has not been demonstrated in a single system. Available gene expression and protein datasets from sarcopenic muscle broadly support these predictions, though direct experimental validation in human tissue remains pending. This complex-centric framework recasts AKT ubiquitination as an integrated regulatory framework. Each structurally autonomous interface may represent a potentially distinct target for muscle-wasting conditions that currently lack approved therapies.