TXNIP-mediated crosstalk between oxidative stress and glucose metabolism

Abstract

Thioredoxin-interacting protein (TXNIP) has emerged as a key player in cancer and diabetes since it targets thioredoxin (TRX)-mediated redox regulation and glucose transporter (GLUT)-mediated metabolism. TXNIP consists of two arrestin (ARR, N-ARR and C-ARR) domains at its amino-terminus and two PPxY (PY) motifs and a di-leucine (LL) motif for endocytosis at its carboxyl-terminus. Here, we report that TXNIP shuffles between TRX and GLUTs to regulate homeostasis of intracellular oxidative stress and glucose metabolism. While TXNIP functions as a gatekeeper of TRX by default, it robustly interacted with class I GLUTs through its C-ARR domain upon increase of intracellular reactive oxygen species. This interaction prompted the surface expression downregulation and lysosomal degradation of GLUTs by its carboxyl-terminal LL endocytic signaling motif to attenuate glucose uptake. Consequently, TXNIP expression significantly limited glucose uptake, leading to the suppression of glycolysis, hexosamine biosynthesis, and the pentose phosphate pathway. Our findings establish a fundamental link between ROS and glucose metabolism through TXNIP and provide a promising target for the drug development against GLUT-related metabolic disorders.

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP

“…In support of this candidacy, multiple studies have documented that TXNIP, a member of the alpha-arrestin family, can block cellular glucose uptake [ 35 , 37 , 38 , 47 ]. One mechanism by which this occurs is via direct interaction of TXNIP with GLUT1 (encoded by SLC2A1 ) and GLUT4 (encoded by SLC2A4 ), which in turn promotes their endocytosis, thereby lowering their capacity to import glucose [ 52 , 53 , 54 , 55 , 56 ]. Both of these transporters are reported to play important roles in cancer cell metabolism [ 57 , 58 , 59 ].…”