Abstract
Stress granules (SGs) are cytoplasmic RNA–protein aggregates formed in response to inhibition of translation initiation. SGs contribute to the stress response and are implicated in a variety of diseases, including cancer and some forms of neurodegeneration. Neurodegenerative diseases often involve chronic phosphorylation of eukaryotic initiation factor 2α (eIF2α), with deletions of eIF2α kinases or treatment with eIF2α kinase inhibitors being protective in some animal models of disease. However, how and why the integrated stress response (ISR) is activated in different forms of neurodegeneration remains unclear. Because neuroinflammation is common to many neurodegenerative diseases, we hypothesized that inflammatory factors contribute to ISR activation in a cell-nonautonomous manner. Using fluorescence microscopy and immunoblotting, we show here that the endogenously produced product of inflammation, 15-deoxy-Δ12,14-prostaglandin J2 (15-d-PGJ2), triggers eIF2α phosphorylation, thereby activating the ISR, repressing bulk translation, and triggering SG formation. Our findings define a mechanism by which inflammation activates the ISR in a cell-nonautonomous manner and suggest that inhibition of 15-d-PGJ2 production might be a useful therapeutic strategy in some neuroinflammatory contexts.
Highlights
Stress granules (SGs) are cytoplasmic RNA–protein aggregates formed in response to inhibition of translation initiation
15-d-PGJ2 has been suggested to inhibit eIF4A, it was originally observed that this prostaglandin can induce P-eIF2␣ [10, 28]
We present several lines of evidence showing that the prostaglandin 15-d-PGJ2 represses bulk translation and triggers stress granules (SGs) formation through phosphorylation of eIF2␣
Summary
15-d-PGJ2 has been suggested to inhibit eIF4A, it was originally observed that this prostaglandin can induce P-eIF2␣ [10, 28]. An important result was that, when cells were treated with 5 nM ISRIB, SGs that formed because of NaAsO2 or 15-d-PGJ2 stresses disappeared within 5 min, whereas PatA SGs were resistant to ISRIB treatment (Fig. 1, A and C) This suggests that 15-d-PGJ2 inhibits translation and promotes SG formation through eIF2␣ phosphorylation and not through inhibition of eIF4A function. We reproduced earlier results showing that NaAsO2 translation repression depends on HRI [9] and that the 26S proteasomal inhibitor MG132 induces translation repression through multiple eIF2␣Ks (Fig. S3, A and B) [9] Taken together, these observations argue that 15-d-PGJ2 activates multiple eIF2␣Ks and that those act together to phosphorylate eIF2␣, repress translation, and trigger SG formation. We suggest that 15-d-PGJ2 modifies and inhibits numerous cellular proteins, such as HSP90, PP1, tRNA synthetases, 26S proteasome subunits, mitochondrial proteins, and translation initiation factors (Fig. S2A), that, in combination, lead to multipronged activation of the ISR [2, 26, 31, 32]
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