Abstract
The integrated stress response (ISR) is activated by diverse forms of cellular stress, including endoplasmic reticulum (ER) stress, and is associated with diseases. However, the molecular mechanism(s) whereby the ISR impacts on differentiation is incompletely understood. Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide insight into the impact of the ISR on cell fate. We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9. Chondrocyte survival is enabled, cell autonomously, by CHOP and dual CHOP-ATF4 transactivation of Fgf21. Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR emerges as a rationale therapeutic strategy for stress-induced skeletal disorders.
Highlights
The Integrated Stress Response (ISR) is a eukaryotic cellular stress response, aiming to restore cellular homeostasis upon different types of extrinsic or intrinsic stresses
To investigate the effect of endoplasmic reticulum (ER) stress on the transcriptome of HCs, the proximal tibial growth plates from 10-day-old WT and 13del mice were fractionated into sub-populations representing proliferating (PZ), prehypertrophic and hypertrophic chondrocytes (HZ) (Figure 1A; Figure 1—figure supplement 1B)
Using Motif enrichment analysis, we found that the binding motifs of CHOP and Activating Transcription Factor 4 (ATF4) were highly enriched in Cluster I, but not those for Xbp1S or activating transcription factor 6 (ATF6) (Figure 1F and Supplementary file 5)
Summary
The Integrated Stress Response (ISR) is a eukaryotic cellular stress response, aiming to restore cellular homeostasis upon different types of extrinsic or intrinsic stresses. The ISR is primarily a pro-survival homeostatic program, aiming to optimize the adaptive cellular response to stress, exposure to severe stress, either in intensity or duration, will overwhelm the capacity of this adaptive response and drive signaling toward cell death. The key early controlling step in the ISR is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2a) by one of four members of eIF2a kinase family: protein kinase R (PKR), PKR-
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