Our results indicate that in mammalian cells, RIDD requires an active Ire1 nuclease domain but does not, per se, depend on Ire1's kinase activity. ER stress-dependent degradation of RNAs by hIre1-I642G was seen at concentrations of 1NM-PP1 1.5-fold higher than those that inhibited the kinase activity of the protein in vitro (Papa et al., 2003) and sixfold higher than those that inhibited kinase activity in HEK293 cells (Lin et al., 2007) . These data, together with the observation that RIDD does not require new transcription, are consistent with a direct mechanism of mRNA target cleavage by Ire1, although we cannot rule out an alternative role for Ire1's nuclease activity and/or the involvement of other nucleases.