REGULATION OF MRNA TURNOVER DURING ER STRESS

The UPR upregulates hundreds of genes involved in the secretory pathway, and reduces the protein folding load on the ER by attenuating translation. We discovered that mRNA decay is also broadly regulated by the UPR; fly cells subjected to ER stress degrade mRNAs associated with the ER membrane. Surprisingly, this effect was dependent on Ire1, a conserved sensor of ER stress and major player in the UPR, but was independent of Ire1’s only known downstream target, the transcription factor Xbp1. This opened up the possibility that Ire1 could have physiological and/or pathological effects beyond those known for Xbp1. We went on to show that this pathway, named Regulated Ire1-Dependent Decay (RIDD), is conserved in mammalian cells and is dependent on the cytosolic-facing ribonuclease activity of Ire1.  

In fly cells, localization to the ER membrane is necessary and sufficient for degradation by RIDD, and almost all mRNAs that experimentally fractionate with the ER are degraded faster during ER stress. This broad, localization-based specificity is consistent with our overall view of RIDD’s function in flies; degradation of these mRNAs would temporarily relieve the protein folding load on the ER and sensitize cells to the massive transcriptional remodeling induced by the UPR.

The specificity of RIDD pathway in mammalian cells is very different; only a handful of mRNAs are degraded by RIDD. Our 2015 paper shows that mammalian RIDD targets rely on specific stem-loop structures for their degradation by Ire1. Furthermore, these stem-loops must be translationally attenuated in order for Ire1 to cleave. For several RIDD targets, this leads to a dependence on a second sensor of ER stress, Perk, which attenuates translation initiation. Thus Perk regulates the RIDD pathway in a substrate-specific manner, potentially limiting its scope both spatially and temporally.

The increased specificity and reduced number of RIDD targets in mammalian cells led to the obvious question: how is this pathway helping cells cope with ER stress? Or is it? See the next section to find out…