Regulated Ire1-dependent decay of messenger RNAs in mammalian cells

Hollien, Julie; Lin, Jonathan H.; Li, Han; Stevens, Nicole; Walter, Peter; Weissman, Jonathan S.

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.