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♦ See referenced article, J. Biol. Chem. 2011, 286, 29139–29145
Thioredoxin-interacting protein (Txnip) is a known mediator of metabolism, having been shown to inhibit adipogenic differentiation in vivo. However, its mechanism for inhibition has remained unclear, although most research has focused on its ability to regulate cellular redox potential via inhibition of thioredoxin (TXN). In their Paper of the Week, Chutkow and Lee uncover a novel regulatory interaction between TXN and Txnip, demonstrating that TXN actually binds and stabilizes Txnip, thus preventing ubiquitin-mediated degradation and allowing Txnip to inhibit adipogenesis. Using a Txnip mutant (C247S) that is unable to bind TXN, the authors found that Txnip was degraded much more rapidly in the absence of TXN binding. Overexpression of TXN prevented Txnip breakdown and inhibited adipogenesis, whereas addition of adipogenic stimulants such as insulin caused increased Txnip degradation. Finally, the researchers mutated two C-terminal PPXY motifs in Txnip that are targets for the E3 ubiquitin ligase Itch, rendering Txnip resistant to degradation and inhibiting adipogenesis, even in the absence of TXN. By highlighting the protein-stabilizing effects of TXN on Txnip, these findings pave the way for uncovering how Txnip is able to inhibit adipogenesis directly.