Thioredoxin-independent Regulation of Metabolism by the α-Arrestin Proteins

Abstract

Thioredoxin-interacting protein (Txnip), originally characterized as an inhibitor of thioredoxin, is now known to be a critical regulator of glucose metabolism in vivo. Txnip is a member of the ␣-arrestin protein family; the ␣-arrestins are related to the classical ␤-arrestins and visual arrestins. Txnip is the only ␣-arrestin known to bind thioredoxin, and it is not known whether the metabolic effects of Txnip are related to its ability to bind thioredoxin or related to conserved ␣-arrestin function. Here we show that wild type Txnip and Txnip C247S, a Txnip mutant that does not bind thioredoxin in vitro, both inhibit glucose uptake in mature adipocytes and in primary skin fibroblasts. Furthermore, we show that Txnip C247S does not bind thioredoxin in cells, using thiol alkylation to trap the Txnipthioredoxin complex. Because Txnip function was independent of thioredoxin binding, we tested whether inhibition of glucose uptake was conserved in the related ␣-arrestins Arrdc4 and Arrdc3. Both Txnip and Arrdc4 inhibited glucose uptake and lactate output, while Arrdc3 had no effect. Structure-function analysis indicated that Txnip and Arrdc4 inhibit glucose uptake independent of the C-terminal WW-domain binding motifs, recently identified as important in yeast ␣-arrestins. Instead, regulation of glucose uptake was intrinsic to the arrestin domains themselves. These data demonstrate that Txnip regulates cellular metabolism independent of its binding to thioredoxin and reveal the arrestin domains as crucial structural elements in metabolic functions of ␣-arrestin proteins.

MondoA Senses Non-glucose Sugars

“…One well characterized direct and glucose-induced target for MondoA is thioredoxin-interacting protein (TXNIP). TXNIP has several functions (8,9), one of which is its potent negative regulation of glucose uptake (10,11). Collectively, these data suggest a model where MondoA senses elevations in Glc-6-P and activates TXNIP transcription, thereby initiating a negative feedback mechanism that restricts further glucose uptake (1,4,7,12).…”

Redox Regulation by Nuclear Factor Erythroid 2-Related Factor 2: Gatekeeping for the Basal and Diabetes-Induced Expression of Thioredoxin-Interacting Protein

“…In addition, TXNIP is required for the development of natural killer cells, which is disrupted in TXNIPdeficient mice . As a member of the mammalian ␣-arrestin proteins, TXNIP contains an arrestin domain that exhibits some metabolic regulatory activities independently of Trx binding (Patwari et al, 2009).…”

Posttranslational regulation of thioredoxin-interacting protein

“…Of the six known mammalian members of the family, Txnip is the only one that binds to thioredoxin, yet other members of the family have been shown to alter glucose metabolism (Patwari et al 2009). This strengthens the concept that Txnip belongs to a new class of metabolic regulators that can operate independently of thioredoxin (Patwari et al 2009). One of the outstanding properties of Txnip is its ability to modulate insulin sensitivity.…”