In contrast to XBP-1 splicing and ERdj4 induction, no degradation of RIDD substrates was observed with 1NM-PP1 alone, indicating that XBP-1 splicing and RIDD are separable functions of Ire1 and have distinct requirements for activation (Fig. 4, D and E) . Treatment of cells expressing Ire1-I642G with DTT or Tm alone (in the absence of 1NM-PP1) had very BiP, an ER chaperone which binds Ire1 and is titrated off by misfolded proteins during ER stress. A second possibility is that other factors activated by ER stress are necessary for RIDD. Although new transcription of such a factor is not required (Fig. 2) , there may be proteins recruited or activated by ER stress that are important for mRNA decay but not for splicing. Finally, the complement of mRNAs available for targeting to this decay pathway may change upon subjecting cells to ER stress. Certain signal sequences are sensitive to the ER folding environment and influence how associated ribosomes partition between the ER and cytoplasm (Kang et al., 2006) ; thus, a substantial change in the pool of mRNAs associated with the ER membrane under stress conditions could affect the RIDD pathway.