However, our data also indicate that activation of Ire1's nuclease is not sufficient for RIDD. This observation represents a mechanistic divergence between RIDD and Ire's well-established role in XBP-1 splicing, which is induced by 1NM-PP1 activation of hIre1-I642G. There are several potential explanations for this. It may be that Ire1 assumes a distinct conformation or oligomerization state when activated by 1NM-PP1 versus ER stress and that although the former is sufficient for splicing XBP-1, the latter is required for RIDD. For example, it was recently found that yeast Ire1 forms higher order oligomers that lead to higher levels of RNase activity (Aragon et al., 2009; Korennykh et al., 2009) . Such oligomers may form only in the presence of misfolded proteins or, conversely, in the absence of binding to relative mRNA abundance for ERdj4 and Blos1 (H) in various concentrations of 1NM-PP1 and/or DTT. Measurements are as described for A and B. (A-H) Cells were treated with 2 mM DTT, 3 µg/ml Tm, and/or 7 µM 1NM-PP1 for 5 h unless otherwise indicated. The means and SD for three to five independent experiments are shown.