1. SCF-SKP2 E3 ubiquitin ligase links mTORC1/ER stress/ISR with YAP activation in murine renal cystogenesis
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Panda, Dibyendu K., Bai, Xiuying, Zhang, Yan, Stylianesis, Nicholas A., Koromilas, Antonis E., Lipman, Mark L., and Karaplis, Andrew C.
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Gene expression -- Health aspects ,Cellular proteins -- Health aspects ,Polycystic kidney disease -- Care and treatment -- Development and progression -- Genetic aspects ,Health care industry - Abstract
The Hippo pathway nuclear effector Yes-associated protein (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1), driven by ERK1/2 and PI3K/AKT cascades, induced ER proteotoxic stress. To reduce this stress by reprogramming translation, the protein kinase R-like ER kinase- eukaryotic initiation factor 2[alpha] (PERK/eIF2[alpha]) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2[alpha] drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2[alpha] phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress/ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan impeded these processes. Restoring ER homeostasis and/or interfering with the SKP2-YAP interaction represent potential therapeutic avenues for stemming the progression of renal cystogenesis., Introduction The primary cilium is a single, nonmotile sensory organelle present at the cell surface. It senses mechanical and chemical environmental cues and conveys these external signals to the cell's [...]
- Published
- 2022
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