Review
Getting RIDD of RNA: IRE1 in cell fate regulation

https://doi.org/10.1016/j.tibs.2014.02.008Get rights and content

Highlights

  • XBP1 splicing and RIDD activities are differentially regulated functions of the UPR transducer IRE1.

  • RIDD is a conserved ancestral mechanism regulating proteostasis in different eukaryotic phyla.

  • RIDD has a basal activity that is required to maintain ER homeostasis.

  • XBP1 splicing and RIDD produce opposite effects on cell fate in cells subjected to ER stress.

Inositol-requiring enzyme 1 (IRE1) is the most conserved transducer of the unfolded protein response (UPR), a homeostatic response that preserves proteostasis. Intriguingly, via its endoribonuclease activity, IRE1 produces either adaptive or death signals. This occurs through both unconventional splicing of XBP1 mRNA and regulated IRE1-dependent decay of mRNA (RIDD). Whereas XBP1 mRNA splicing is cytoprotective in response to endoplasmic reticulum (ER) stress, RIDD has revealed many unexpected features. For instance, RIDD cleaves RNA at an XBP1-like consensus site but with an activity divergent from XBP1 mRNA splicing and can either preserve ER homeostasis or induce cell death. Here we review recent findings on RIDD and propose a model of how IRE1 RNase activity might control cell fate decisions.

Section snippets

IRE1, a highly conserved mediator of the UPR

The ER is an organelle comprising a luminal network that is the site of production of secretory and membrane-anchored proteins. It controls the correct folding of newly synthesized proteins, through the action of numerous ER-resident molecular chaperones and folding catalysts, and the degradation of improperly folded proteins [ER-associated degradation (ERAD)]. Twenty-five years ago, Kozutsumi and colleagues discovered a homeostatic pathway in mammalian cells that orchestrates adaptation to

RIDD is sequence specific

In S. cerevisiae, HAC1 mRNA splicing occurs by a nonconventional mechanism catalyzed by the coordinated action of IRE1 and the tRNA ligase RLG1 1, 2. The removal of the intron resembles that of pre-tRNA splicing, leaving free 2′,3′-cyclic phosphates. In addition, small stem–loop structures localized at both spliced junctions are required for IRE1 cleavage 1, 2 (Figure 1A). The ligase that joins the XBP1 exon fragments in other species remains to be identified. Several structural studies of IRE1

IRE1 preferentially targets ER-localized mRNAs

The first mRNAs found to be cleaved by IRE1 encoded proteins translated and matured in the ER, which led to the hypothesis that RIDD would exclusively target mRNAs that, on cotranslational import of their products into the ER, come within the vicinity of IRE1 8, 10. Interestingly, all of the identified IRE1β RNase targets encode ER-localized/secretory proteins (Table 2). By contrast, the described IRE1α RNase-target metazoan RNAs (Table 1) encode 64% ER-localized/secretory proteins and 36%

RIDD activity increases under ER stress and induces cell death

Recently, Han and coworkers showed that XBP1 mRNA splicing and RIDD activities are induced through two different IRE1 activation modes: pseudokinase and phosphotransfer, respectively [9]. Another intriguing observation from this study was that the cytoprotective effect of IRE1 requires only pseudokinase activation and XBP1 splicing, whereas apoptosis needs phosphotransfer activation and is RIDD dependent [9]. Han and coworkers used an IRE1 mutant (I642G) with an engineered nucleotide-binding

Basal RIDD activity is required for ER homeostasis

In the past few years, many studies performed in various organisms have demonstrated that IRE1 has a basal RIDD activity that is necessary for ER homeostasis maintenance. Because XBP1 mRNA splicing is a marker of ER stress, we here define basal RIDD as detectable RIDD activity without induction of XBP1 mRNA splicing; therefore, in the absence of ER stress. The RIDD-dependent molecular mechanisms involved in ER homeostasis maintenance are described in Box 2. In Caenorhabditis elegans, IRE1 loss

RIDD from ER homeostasis control to cell death signaling

We propose a model for the activation of both IRE1 RNase activities, integrating the information collected above (Figure 2). The different mechanisms reported to activate the different IRE1 orthologs and paralogs are described in Box 1 and Figure 2A. Under basal conditions, XBP1 mRNA is not spliced. Under low ER stress, XBP1 mRNA splicing increases progressively to reach a peak and then declines after prolonged stress 20, 47, 48, 49, 50 (Figure 2B). By contrast, RIDD displays constitutive

Concluding remarks

IRE1 is capable of promoting survival or death depending on the stress intensity or duration [3]. XBP1 mRNA splicing has been clearly shown, in various model systems, as cytoprotective in response to ER stress 1, 48. Since the first report on RIDD in 2006 [8], accumulating evidence has indicated that: (i) RIDD is sequence specific (Figure 1B and Tables 1, 2, and 3); (ii) RIDD targets mRNA encoding proteins that are localized in the cytosol, nucleus, or ER or secreted (Figure 1C); (iii) RIDD has

Acknowledgments

The authors apologize to all colleagues whose work could not be cited owing to space limitations. This work was supported by the Ghent University GROUP-ID (Ghent Researchers On Unfolded Proteins in Inflammatory Disease) multidisciplinary research platform. The work was funded by grants from INSERM, INCa, and CRLCC Eugène Marquis to E.C.; M.M. was supported by a postdoctoral fellowship from FWO.

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