Salicylates Trigger Protein Synthesis Inhibition in a Protein Kinase R-like Endoplasmic Reticulum Kinase-dependent Manner

Aristóbolo M Silva,Die Wang,Anton A Komar,Beatriz A Castilho,Bryan R.G Williams

doi:10.1074/jbc.m609996200

Abstract

The non-steroidal anti-inflammatory drug aspirin and its metabolite, sodium salicylate, have profound effects on cellular protein synthesis and cell physiology. However, the underlying mechanism by which they cause these responses remains unclear. We show here that salicylates induce phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha), resulting in the inhibition of mRNA translation in cells. Exposure of cells to acetyl salicylic acid resulted in strong activation of eIF2alpha stress-activated protein kinase R-like endoplasmic reticulum kinase (PERK). Analysis of fibroblasts with a targeted deletion of the perk gene revealed that PERK is indispensable for triggering the phosphorylation of eIF2alpha as well as the inhibition of protein synthesis induced by salicylates. Although salicylate treatment did not trigger activation of inositol-requiring enzyme 1, there was an increased expression of the pro-apoptotic transcription factor CHOP-(gadd153), a downstream event to eIF2alpha phosphorylation known to mediate endoplasmic reticulum stress-mediated responses. Thus, salicylates selectively trigger an endoplasmic reticulum stress-responsive signaling pathway initiated through activation of PERK to induce their cellular effects.

Highlights

The non-steroidal anti-inflammatory drugs sodium salicylate and aspirin have been widely used to prevent and treat a number of diseases including inflammation and cancer [1, 2]
Our results demonstrate that inhibition of protein synthesis by salicylates correlates with phosphorylation of eIF2␣ (Figs. 1 and 2A)
We found that PKR-like endoplasmic reticulum (ER) kinase (PERK) was activated by salicylates (Fig. 4C) and was required to promote the inhibition of global protein synthesis (Fig. 5)

Summary

Introduction

The non-steroidal anti-inflammatory drugs sodium salicylate and aspirin have been widely used to prevent and treat a number of diseases including inflammation and cancer [1, 2]. Salicylate treatment did not trigger activation of inositol-requiring enzyme 1, there was an increased expression of the pro-apoptotic transcription factor CHOP(gadd153), a downstream event to eIF2␣ phosphorylation known to mediate endoplasmic reticulum stress-mediated responses.

Results

Conclusion