TXNIP action has been implicated in diverse physiological and pathological contexts. TXNIP was first described as an inhibitor of thioredoxin, an anti-oxidant enzyme that catalyzes cysteine-thiol disulfide exchange (Nishiyama et al., 1999; Patwari et al., 2006; Yamanaka et al., 2000). Increased TXNIP levels renders cells susceptible to oxidative stress. Thus, we predicted, and confirmed, that increasing TXNIP levels would generate reactive oxygen species (ROS); we further predicted, and confirmed, that IRE1α hyper-activation, or irremediable ER stress, would also spontaneously generate ROS (Figure S7A–F). As ROS enhance activation of NLRP3 inflammasome, they may further amplify effects of the IRE1α-TXNIP node to increase sterile inflammation.
