The study investigates the regulated Ire1-dependent decay (RIDD) of messenger RNAs (mRNAs) in mammalian cells, particularly mouse fibroblasts. RIDD is a mechanism that responds to endoplasmic reticulum (ER) stress by degrading mRNAs encoding membrane and secreted proteins. The researchers used wild-type and mutant variants of Ire1, a transmembrane protein activated by protein misfolding in the ER, to demonstrate that the nuclease activity of Ire1 is essential for both XBP-1 splicing and RIDD. However, these two functions can be differentially triggered, indicating a complex mechanism of Ire1 activation. The study also shows that RIDD can be induced by a small adenosine triphosphate analogue, 1NM-PP1, which activates Ire1 without its kinase activity. This suggests that RIDD may not depend on the kinase activity of Ire1 and highlights the complexity of the unfolded protein response (UPR), where different conditions in the ER lead to distinct outputs from Ire1. The findings provide insights into how cells use a multitered mechanism to manage ER stress and maintain cellular homeostasis.The study investigates the regulated Ire1-dependent decay (RIDD) of messenger RNAs (mRNAs) in mammalian cells, particularly mouse fibroblasts. RIDD is a mechanism that responds to endoplasmic reticulum (ER) stress by degrading mRNAs encoding membrane and secreted proteins. The researchers used wild-type and mutant variants of Ire1, a transmembrane protein activated by protein misfolding in the ER, to demonstrate that the nuclease activity of Ire1 is essential for both XBP-1 splicing and RIDD. However, these two functions can be differentially triggered, indicating a complex mechanism of Ire1 activation. The study also shows that RIDD can be induced by a small adenosine triphosphate analogue, 1NM-PP1, which activates Ire1 without its kinase activity. This suggests that RIDD may not depend on the kinase activity of Ire1 and highlights the complexity of the unfolded protein response (UPR), where different conditions in the ER lead to distinct outputs from Ire1. The findings provide insights into how cells use a multitered mechanism to manage ER stress and maintain cellular homeostasis.