The eIF2α kinase HRI in innate immunity, proteostasis, and mitochondrial stress

Abstract

The integrated stress response (ISR) is an evolutionary conserved stress response pathway that leads to a global arrest in translation as well as to the expression of specific genes, such as the transcription factor ATF4, to promote cellular recovery. The central nexus of this pathway is the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2a) by one of the four eIF2a kinases that sense specific cellular stressors. The heme-regulated inhibitor (HRI) is one of these kinases, and it was initially reported to be activated in response to heme deprivation. Nevertheless, further studies have established that cytosolic proteotoxicity, resulting from oxidative or osmotic stress, heat shock, and proteasome inhibition, is the predominant trigger for HRI to induce the ISR. In this review, we present newly identified functions of HRI in innate immunity, proteostasis, and mitochondrial stress. Indeed, HRI-mediated signaling defines a novel cytosolic unfolded protein response (cUPR) required for the proper formation of some innate immune signalosomes and the control of toxic protein aggregates, and this eIF2a kinase also serves as a relay for mitonuclear communication after a mitochondrial stress. Abbreviations eIF2a, alpha subunit of eukaryotic translation initiation factor 2; GCN2, general control nonderepressible 2; HRI, heme-regulated inhibitor; ISR, integrated stress response; PERK, PKR-like ER kinase; PKR, double-stranded RNA (dsRNA)-dependent protein kinase.

Research Progress on the Structure and Function of G3BP

“…The classical assembly pathway of SGs is mainly mediated by the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2a). The elF2a kinase family includes PKR endoplasmic reticulum kinase (PERK/PEK) (28), protein kinase R (PKR) (29), general control nonderepressible 2 (GCN2) (30), and heme-regulated inhibitor (HRI) (31,32). Furthermore, eIF2a is phosphorylated by one or more of these kinases, thereby reducing the concentration of the elF2-GTP-tRNA Met ternary complex.…”

Sensing, signaling and surviving mitochondrial stress

“…A more general role for HRI in cytosolic protein homeostasis beyond heme can be rationalized by its interplay with heat shock factors, including HSP90, HSPA8 and HSPB8 [160][161][162]. This led to the hypothesis that HRI functions in a cytosolic unfolded protein response (cUPR) that can be triggered by inhibition of the UPS or by large protein aggregates like such formed by α-synuclein and several innate immune signalosomes [160,163]. These signaling platforms, also known as SMOCs (supramolecular organizing centers), are for instance utilized during antiviral signaling of MAVS at the mitochondrial surface [164] or peptidoglycan sensing via NOD1/2, and seem to involve HRI [160].…”

Hiding in Plain Sight: Formation and Function of Stress Granules During Microbial Infection of Mammalian Cells

“…An interesting connection between innate immunity and SGs is the ability of eIF2α kinases to regulate the signalosomes, which have been shown to have the ability to form amyloid fibrils ( Sohn and Hur, 2016 ; Girardin et al, 2020 ). These include the NLRP3 and AIM2 inflammasome, the nodosome, as well as MAVS, TRIF, and RIPK1/RIPK3 amyloid-like fibrils.…”