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Updated: Aug 14, 2026

Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene
Heather P Harding1, Yuhong Zhang, Sonya Khersonsky
1Skirball Institute of Biomolecular Medicine, New York University, New York, New York 10016, USA.
Abstract:
Phosphorylation of translation initiation factor 2alpha (eIF2alpha) coordinates a translational and transcriptional program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. A screen for small molecule activators of the ISR identified two related compounds that also activated sterol-regulated genes by blocking cholesterol biosynthesis at the level of CYP51. Ketoconazole, a known CYP51 inhibitor, had similar effects, establishing that perturbed flux of precursors to cholesterol activates the ISR. Surprisingly, compound-mediated activation of sterol-regulated genes was enhanced in cells with an ISR-blocking mutation in the regulatory phosphorylation site of eIF2alpha. Furthermore, induction of the ISR by an artificial drug-activated eIF2alpha kinase reduced the level of active sterol regulatory element binding protein (SREBP) and sterol-regulated mRNAs. These findings suggest a mechanism by which interactions between sterol metabolism, the ISR, and the SREBP pathway affect lipid metabolism during ER stress.
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