To limit false positives, we applied a series of strict criteria for identifying the most likely RIDD targets (see Materials and methods); the results are shown in Table I . We confirmed the regulation of several of these targets by reverse transcription followed by quantitative real-time PCR (qPCR; Fig. 1 and Fig. S1 ). To determine whether the down-regulation was a general response to ER stress or was restricted to DTT, we also treated cells with tunicamycin (Tm), which inhibits N-linked glycosylation or thapsigargin, which disrupts calcium homeostasis. All candidate RIDD (see Fig. 3 B). Both cell lines strongly induced immunoglobinbinding protein (BiP), an abundant ER chaperone, in response to ER stress ( Fig. 1) , which is in agreement with previous observations that BiP induction is Ire1 independent in mouse fibroblasts (Lee et al., 2002) . As expected, induction of ERdj4, a transcriptional target of the Ire1/XBP-1 branch of the UPR , was stronger in the hIre1 R cells compared with Ire1 / cells, especially in response to DTT, a reducing agent which disrupts disulfide bond formation in the ER (Fig. 1 A) .