A (dis)integrated stress response: Genetic diseases of eIF2α regulators

Abstract

The integrated stress response (ISR) is a conserved mechanism by which eukaryotic cells remodel gene expression to adapt to intrinsic and extrinsic stressors rapidly and reversibly. The ISR is initiated when stress-activated protein kinases phosphorylate the major translation initiation factor eukaryotic translation initiation factor 2ɑ (eIF2ɑ), which globally suppresses translation initiation activity and permits the selective translation of stress-induced genes including important transcription factors such as activating transcription factor 4 (ATF4). Translationally repressed messenger RNAs (mRNAs) and noncoding RNAs assemble into cytoplasmic RNA-protein granules and polyadenylated RNAs are concomitantly stabilized. Thus, regulated changes in mRNA translation, stability, and localization to RNA-protein granules contribute to the reprogramming of gene expression that defines the ISR. We discuss fundamental mechanisms of RNA regulation during the ISR and provide an overview of a growing class of genetic disorders associated with mutant alleles of key translation factors in the ISR pathway.

Epigenetic regulation of translation repression in ferroptosis, and a role of Alternative splicing and tRNA methylation

“…Knockdown of MESH1 led to activated of ISR, endoplasmic reticulum (ER) stress, phosphorylation of eIF2α and protected against Erastin induced ferroptosis 12 . eIF2α phosphorylation suppresses global mRNA translation 75 . Such global translation suppression is associated by selective translation of stress responsive genes such as GSH 18 via mRNA stabilization and selective tRNA enrichment 18 .…”

The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis

“…From a cellular perspective, the inhibition of translation promotes the formation of stress granules (SGs), which are microscopically visible assemblies that form through liquid-liquid phase separation. SGs are composed of translationally arrested mRNAs and RNA-binding proteins, as well as some translation factors (reviewed by English, Green, and Moon, 2022 [ 43 ]). SGs form rapidly upon eIF2alpha (eIF2a) phosphorylation and cluster over time; when translation rates are restored, SGs are dynamically “dissolved”.…”

“…In response to transient, ISR-inducing stresses, TDP43 is also recruited to SGs [ 145 , 146 , 147 , 148 ]. While the nature of TDP43 incorporation into SGs is reversible (and distinct from the stable, insoluble inclusions that feature advanced pathogenic TDP43 aggregation) it has been proposed that chronic or repeated ISR activation/SGs formation could favour the initiation of pathological TDP43 aggregation [ 43 , 104 , 149 , 150 ].…”

Signaling plasticity in the integrated stress response

“…For example, PKR −/− mice develop normally, while knock-out of its sister kinase PERK leads to strong growth retardation (Table 1). Similarly, patients with ISR mutations can exhibit distinctive clinical manifestations [reviewed in English et al (2022)]. Mutations that result in ISR activation, for instance, lead to growth impairment in the case of CReP, but leukodystrophy (known as Vanishing White Matter Disease) in sensitivities of different brain cell types (Wong et al, 2019), and celltype specific ISR signaling differences can be profound amongst cell types sharing ontogeny (Wolzak et al, 2022).…”