Intracellular Shuttling and Mitochondrial Function of Thioredoxin-interacting Protein

Abstract

The thioredoxin-interacting protein TXNIP is a ubiquitously expressed redox protein that promotes apoptosis. Recently, we found that TXNIP deficiency protects against type 1 and 2 diabetes by inhibiting beta cell apoptosis and maintaining pancreatic beta cell mass, indicating that TXNIP plays a key role in beta cell biology. However, very little is known about the intracellular localization and function of TXNIP, and although TXNIP has been thought to be a cytoplasmic protein, our immunohistochemistry studies in beta cells surprisingly revealed a nuclear TXNIP localization, suggesting that TXNIP may shuttle within the cell. Using immunohistochemistry/confocal imaging and cell fractionation/co-immunoprecipitation, we found that, under physiological conditions, TXNIP is localized primarily in the nucleus of pancreatic beta cells, whereas oxidative stress leads to TXNIP shuttling into the mitochondria. In mitochondria, TXNIP binds to and oxidizes Trx2, thereby reducing Trx2 binding to ASK1 and allowing for ASK1 phosphorylation/activation, resulting in induction of the mitochondrial pathway of apoptosis with cytochrome c release and caspase-3 cleavage. TXNIP overexpression and Trx2 (but not cytosolic Trx1) silencing mimic these effects. Thus, we discovered that TXNIP shuttles between subcellular compartments in response to oxidative stress and identified a novel redox-sensitive mitochondrial TXNIP-Trx2-ASK1 signaling cascade.

TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1

“…However, a significant portion (410%) of endogenous Redd1 is localized to the mitochondria, which regulates reactive oxygen species (ROS) (Horak et al, 2010). TXNIP is present in both the cytoplasm (Junn et al, 2000;Schulze et al, 2002Schulze et al, , 2004 and nucleus (Nishinaka et al, 2004;Saxena et al, 2010). TXNIP has also been reported to be present in mitochondria and has been shown to bind the mitochondrially localized TRX (Oka et al, 2006).…”

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

“…TXNIP binds reduced Trx and prevents it from reducing Prx, thereby blocking cyclic Trx redox reactions. TXNIP has been implicated in the development of type 2 diabetes through several mechanisms, including promoting ␤-cell apoptosis by regulating Trx2 and ASK1 in the mitochondria (Saxena et al, 2010), inhibiting glucose uptake in fat tissue and skeletal muscle to increase insulin resistance (Parikh et al, 2007), stimulating glucose production in the liver (Chutkow et al, 2008), and regulating adipogenesis (Chutkow et al, 2010) and fatty acid utilization (Oka et al, 2006). TXNIP promotes oxidative damage in vascular endothelia to cause vascular pathology (Schulze et al, 2004) and regulates Schwann cell reactions in peripheral nerve repair through a receptor for the advanced glycation end products-TXNIP axis to induce peripheral nerve injury (Sbai et al, 2010).…”

Thioredoxin-Interacting Protein Deficiency Protects against Diabetic Nephropathy

“…[9][10][11][12][13] Under HG conditions, TxNIP has been implicated in impairing ROS scavenging by binding to and attenuating the antioxidant action of thioredoxin, a ubiquitous oxidoreductase. 14 In addition, we recently reported that TxNIP enhances HG-induced mitochondria-derived O 2 2 (superoxide) as well as cellular ROS, at least in part, by augmenting the mitochondrial and cytosolic NADPH oxidase isoform, Nox4, in cultured mesangial cells. 15 Thus, by increasing the generation and decreasing the degradation of ROS, HG-induced TxNIP may contribute to glucotoxicity, as observed by others and our group in pancreatic b cells.…”