In this study, we take advantage of mouse fibroblasts lacking Ire1 activity, both to confirm that RIDD is conserved in mammalian cells and to investigate the functional require- and Fig. S1 ). Although 120 mRNAs fell into this category in the array data, the magnitudes of the changes in expression were generally small (many were twofold or less) compared with those seen in Drosophila cells, where many RNAs were downregulated by 5-10-fold. Despite the relatively small changes for individual messages, the effect of down-regulating mRNAs at the ER surface may profoundly impact the folding burden of the ER. For example, the redistribution of certain nascent proteins from the ER to the cytosol during ER stress significantly impacts cell survival, although the effect on translocation is similar in magnitude to RIDD (Kang et al., 2006) .