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 fact that the two outputs of Ire1's nuclease activity, RIDD and XBP-1 splicing, can be differentially activated reveals an unanticipated complexity in the UPR. Growing evidence suggests that various sensors associated with the UPR are activated under different conditions, allowing for specific responses to different forms of ER stress in different cell types (Gass et al., 2002; DuRose et al., 2006) . This customization of responses may extend to activation within Ire1 itself. Activation of XBP-1 leads to a protective remodeling and expansion of the secretory pathway, whereas RIDD reduces the load of incoming proteins. Under certain physiological situations, e.g., during plasma cell development, activating the XBP-1-dependent remodeling pathway without inducing RIDD may be more beneficial; thus, cells may induce an active state of Ire1 that is similar to the 1NM-PP1-mediated activation described in this study. In contrast, conditions such as viral infection may call for a more destructive response that limits the load of incoming proteins, which is analogous to the effects of reduced translation mediated by the PERK (PKR-like ER kinase) branch of the UPR (Harding et al., 2000) . Intriguingly, both hepatitis C virus and human cytomegalovirus induce Ire1 but appear to block downstream effects of XBP-1 (Tardif et al., 2004; Isler et al., 2005) . However, hepatitis C virus protein production is increased in the absence of Ire1 (Tardif et al., 2004) , suggesting that an alternate activity of Ire1 such as RIDD may be attenuating viral protein synthesis. It remains to be determined what role RIDD may play in viral infection and other physiological stress conditions, but the ability of this pathway to function in mammalian cells and the potential to decouple it from XBP-1 splicing could allow for a more specific and effective response to changing conditions within the ER.