Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression.
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.
Harding
Heather P
HP
Skirball Institute of Biomolecular Medicine, New York University, New York, New York 10016, USA.
Zhang
Yuhong
Y
Khersonsky
Sonya
S
Marciniak
Stefan
S
Scheuner
Donalyn
D
Kaufman
Randal J
RJ
Javitt
Norman
N
Chang
Young-Tae
YT
Ron
David
D
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D015151:Immunoblotting; D007654:Ketoconazole / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic
D015852:Eukaryotic Initiation Factor-2; D008055:Lipids; D012333:RNA, Messenger; D051779:Sterol Regulatory Element Binding Proteins; D013261:Sterols; D002784:Cholesterol; D007654:Ketoconazole