AIHA, autoimmune hemolytic anemia; ANC, absolute neutrophil count; CT, computed tomography; WBC, leukocyte count; PLT, platelet count; ARDS, acute respiratory distress syndrome; ICU, intensive care unit; PEEP, positive end expiratory pressure; NOi, inhaled nitric oxide; ECMO, extracorporeal membrane oxygenation; CRP, C reactive protein. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells Maintenance of endoplasmic reticulum (ER) function is achieved in part through Ire1 (inositol-requiring enzyme 1), a transmembrane protein activated by protein misfolding in the ER. The cytoplasmic nuclease domain of Ire1 cleaves the messenger RNA (mRNA) encoding XBP-1 (X-box–binding protein 1), enabling splicing and production of this active transcription factor. We recently showed that Ire1 activation independently induces the rapid turnover of mRNAs encoding membrane and secreted proteins in Drosophila melanogaster cells through a pathway we call regulated Ire1-dependent decay (RIDD). In this study, we show that mouse fibroblasts expressing wild-type Ire1 but not an Ire1 variant lacking nuclease activity also degrade mRNAs in response to ER stress. Using a second variant of Ire1 that is activated by a small adenosine triphosphate analogue, we show that although XBP-1 splicing can be artificially induced in the absence of ER stress, RIDD appears to require both Ire1 activity and ER stress. Our data suggest that cells use a multitiered mechanism by which different conditions in the ER lead to distinct outputs from Ire1. The ER is responsible for folding and processing proteins entering the secretory pathway and uses a variety of mechanisms to adjust its capacity in response to changes in the folding burden. This collection of mechanisms, termed the unfolded protein response (UPR; Ron and Walter, 2007) , is activated by stress caused by environmental stimuli and diseases such as viral infection (Tardif et al., 2004; Bechill et al., 2008) and multiple myeloma (Carrasco et al., 2007) . In metazoans, components of the UPR are essential for developmental processes requiring high levels of secretion such as the differentiation of plasma cells (Gass et al., 2002; Iwakoshi et al., 2003) and pancreatic  cells (Harding et al., 2001; Zhang et al., 2002) . The UPR restores ER function both by increasing its capacity and decreasing the load of new proteins through transcriptional induction of secretory pathway components and general translational attenuation. One of the key players in the UPR is Ire1 (inositolrequiring enzyme 1), a conserved transmembrane protein with a luminal domain that senses protein misfolding in the ER.