eIF2α phosphorylation: A hallmark of immunogenic cell death

Abstract

Immunogenic cell death (ICD) induced by anticancer chemotherapeutics is usually preceded by premortem stress affecting the endoplasmic reticulum (ER). This ER stress does not reflect a canonical unfolded protein response (UPR) but rather manifests solely at the level of the phosphorylation of eIF2α. eIF2α phosphorylation is hence a quintessential hallmark of ICD that can be detected by immunohistochemistry in tumor samples.

Keywords: ER stress; anthracyclines; cancer; chemotherapy; unfolded protein response.

Figure 1.

(A) The unfolded protein response of the endoplasmic reticulum in normal circumstances. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) provokes the release of heat shock protein family A (Hsp70) member 5 (HSPA5, best known as binding immunoglobulin protein, BiP) and activates simultaneously the three arms of the unfolded protein response (UPR) ((i) EIF2AK3, (best known as PERK)-mediated phosphorylation of eukaryotic initiation factor α (eIF2α), which in turn halts general protein translation but favors the expression of activating transcription factor 4 (ATF4), (ii) the translocation of the ER transmembrane protein activating transcription factor 6 (ATF6) to the Golgi, proteolytic cleavage and the nuclear translocation of its cytosolic fraction (iii) the endoplasmic reticulum to nucleus signaling 1 (ERN, best known as IRE1α)-mediated splicing of X-box binding protein 1 (XBP1) to the XBP1s isoform. The signal transduction issued by the activation of the transcription factors ATF4, ATF6 and XBP1s aim at reestablishing ER homeostasis and cell survival (or the induction of cell death in conditions of enduring ER stress). (B) The unfolded protein response in the context of immunogenic cell death (ICD). First, the non-canonical activation of PERK and possibly other eIF2α kinases triggers the phosphorylation of eIF2α without BiP occupation by misfolded proteins and/or second, ICD-inducers inhibit UPR downstream signals such as ATF4 translation, ATF6 cleavage and the IRE1α−mediated XBP1 splicing.