Discovery of a novel branch of the metazoan UPR involving targeted mRNA destruction


Elegant work pioneered by my UCSF/HHMI colleague and collaborator Peter Walter identified Ire1 as a key ER sensor of misfolded proteins. These studies revealed the canonical activation pathway in which unfolded proteins sensed in the ER lumen induce the cytoplasmic nuclease domain of Ire1 to cleave the mRNA encoding XBP-1 (Hac1 in yeast), enabling splicing and production of active transcription factor. This allows for the remodeling of the ER in response to stress. But transcriptional responses are slow. We found that in metazoans, activation of the Ire1 endonuclease independently induces the rapid turnover of many mRNAs encoding membrane and secreted proteins through a pathway we call regulated Ire1-dependent decay (RIDD). This response is well suited to complement other UPR mechanisms by selectively halting production of proteins that challenge the ER and clearing the translocation and folding machinery for the subsequent remodeling process. More recently, we, and independently the Papa group, provided evidence that cells use a multi-tiered mechanism by which different conditions in the ER lead to distinct outputs (transcriptional versus RIDD) from Ire1. This allows for a nuanced response to different stresses and provides the potential for therapeutics that "surgically" intervene with specific Ire1 outputs, preventing proapoptotic effects while keeping protective outputs intact.