The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

TLDR

ER stress from protein folding disruptions activates the unfolded protein response, mediated by the sensors PERK, ATF6, and IRE1, with PERK phosphorylating eIF2α to suppress global translation while selectively translating ATF4. This study investigates whether the PERK/eIF2α‑P/ATF4 axis is necessary for activating ATF6 and its downstream genes. PERK promotes ATF6 synthesis and its transport from the ER to the Golgi, where proteolytic cleavage activates ATF6. Loss of PERK in liver cells blunts both translational and transcriptional UPR, reduces chaperone levels, perturbs lipid metabolism, heightens apoptosis, and demonstrates that UPR regulatory networks are fully integrated.

Abstract

Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors (PERK, ATF6, and IRE1) implement the UPR. PERK phosphorylation of the α subunit of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins. Phosphorylation of eIF2α (eIF2α∼P) also induces preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α∼P/ATF4 pathway is required not only for translational control, but also for activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated and help explain the diverse biological defects associated with loss of PERK.