LAUSR

Gap junctions (GJs) play a major role in the control of cell structure, function, and metabolism. However, the molecular mechanisms involved are still poorly understood. Given that thioredoxin-interacting protein (TXNIP) regulates a broad range of cellular processes, we tested the possible involvement of TXNIP. Disruption of GJs with several chemical GJ inhibitors or connexin43 (Cx43) siRNA potently suppressed TXNIP, which was preceded by an activation of extracellular signal-regulated kinase (ERK). Inhibition of ERK or its upstream kinase with chemical inhibitors prevented the reduction of TXNIP. On the contrary, activation of ERK with mitogens or phosphatase inhibitors reproduced the suppressive effects of GJs. Further analysis revealed that dysfunction of GJs promoted TXNIP phosphorylation, ubiquitination, and degradation, whereas inhibition of ERK exerted the opposite effects. Moreover, inhibition of GJs elevated Glut1 and enhanced cell resistance to ER stress in a similar way to TXNIP downregulation. Collectively, our study thus characterizes ERK-mediated suppression of TXNIP as a presently unreported mechanism by which GJs regulate cell behaviors.