The UPR sensors IRE1α, PERK, and ATF6 become activated as the earliest signaling events in cells experiencing ER stress. Because TXNIP is induced contemporaneously with PERK and IRE1α activation (Figure S2A), we reasoned that early UPR signaling events may mediate upregulation of TXNIP mRNA and protein. To test this, we treated mouse embryonic fibroblasts (MEFs) deficient for each UPR sensor with either Tm or Tg (Figure 2A). TXNIP mRNA induction is significantly diminished in both Ire1α−/− and Perk−/− MEFs during ER stress, but induction remains unperturbed in Atf6a −/− MEFs. Paralleling this effect, TXNIP protein induction is completely abrogated in Ire1α−/− and Perk−/− MEFs during ER stress (Figure 2B), but unaffected in Atf6a−/− MEFs (Figure S3A).
