Inositol Metabolite Depletion Induces Hallmarks of ER Stress Without Activating the UPR

The unfolded protein response (UPR) is a transcriptional pathway that responds to unfolded proteins in the endoplasmic reticulum (ER) through three well-defined pathways. However, the production of reactive oxygen species (ROS), membrane aberrancy, and the depletion of the sugar, lipid component, and signaling molecule inositol are also linked to UPR activation. While the mechanism for ROS-mediated UPR activation is understood, the mechanism for membrane aberrancy and inositol depletion—believed to be the same—is much less clear. Given inositol depletion’s reduction of several inositol metabolites with divergent roles in the UPR, our study of the transcriptomic changes due to the metabolic depletion of certain inositols attempts to illuminate the poorly understood connections between inositol depletion, membrane aberrancy, and the UPR. We amalgamated and filtered RNA sequencing data from 19 studies knocking out inositol metabolic enzymes and conducted functional analyses. Our results indicated that while protein degradation, membrane stress, and redox stress—all hallmarks of ER stress and heavily associated with the UPR—were transcriptionally supported by inositol metabolite depletion, the UPR was not activated. As a result, inositol depletion studies could carry a confounding noise due to the depletion of inositol products that obfuscates attempts to define inositol’s connections with membrane aberrancy and the UPR. The results of our study urge further research into the consequences of inositol metabolite depletion both to vitiate the resulting concerns about inositol depletion studies and to explain the lack of UPR activation even with the induction of ER stress hallmarks associated with UPR activation.