Review Neuronal Regulation of eIF2a Function in Health and Neurological Disorders 1 2 1,3, Stephanie L. Moon, Nahum Sonenberg, and Roy Parker * A key site of translation control is the phosphorylation of the eukaryotic trans- Highlights lation initiation factor 2a (eIF2a), which reduces the rate of GDP to GTP Phosphorylation of eIF2a is a key reg- ulatory target for translation control exchange by eIF2B, leading to altered translation. The extent of eIF2a phos- that is important in regulating transla- phorylation within neurons can alter synaptic plasticity. Phosphorylation of tion during normal and stress conditions. eIF2a is triggered by four stress-responsive kinases, and as such eIF2a is often phosphorylated during neurological perturbations or disease. Moreover, Emerging data highlight that eIF2a in some cases decreasing eIF2a phosphorylation mitigates neurodegenera- phosphorylation is crucial in neuronal function and impacts synaptic plasti- tion, suggesting that this could be a therapeutic target. Mutations in the g city as well as being inappropriately subunit of eIF2, the guanine exchange factor eIF2B, an eIF2a phosphatase, or increased in numerous neurodegen- in two eIF2a kinases can cause disease in humans, demonstrating the impor- erative diseases. tance of proper regulation of eIF2a phosphorylation for health. Mutations in components of the eIF2a phosphorylation circuit give rise to EIF2a Is a Major Nexus of Translation Regulation in Neurological Health and human diseases, often including neu- Disease rological and/or neurodegenerative pathologies. The regulation of translation is an important aspect of the control of eukaryotic gene expression, and most commonly occurs during the initiation phase of translation. Initiation In model systems of neurological dis- – of translation is a multistep process wherein the mRNA protein complex (mRNP) recruits a ease with perturbed eIF2a function, multifactor complex (MFC) containing the initiation factors eIF1, eIF3, and eIF5, as well as the therapeutic restoration of proper eIF2a control can decrease the severity of eIF2 complex bound to GTP and the initiator tRNA, facilitating delivery of the ternary complex disease via targeting of eIF2a kinases to the 40S ribosomal subunit [1] (Figure 1). The MFC is most commonly recruited to the mRNA or phosphatases, or by mitigating 0 by the eIF4F complex which recognizes and binds to the 5 cap structure and positions the phospho-eIF2a activity. 0 MFC to scan from the 5 end to the AUG initiation codon. Once the AUG is recognized, The regulation of eIF2a phosphoryla- hydrolysis of GTP by eIF2 commits the 40S ribosome to translation initiation and leads to the tion is a promising therapeutic target recruitment of the 60S subunit and entry into the elongation phase of translation initiation. for the treatment of neurological After release of eIF2–GDP from the ribosome, GDP is exchanged for GTP by the guanine diseases. nucleotide exchange factor (GEF) eIF2B, preparing the eIF2 complex for another round of initiation. The exchange of GDP for GTP on the heterotrimeric eIF2 complex by the eIF2B complex has 1 emerged as a major node of translation control (Figure 2). In humans, four distinct kinases can Department of Chemistry and Biochemistry, University of Colorado, be activated by various intracellular cues to phosphorylate the eIF2a subunit of the eIF2 Boulder, CO 80303, USA complex on serine 51 (in humans) [2,3]. Generally, PERK (protein kinase R-like endoplasmic 2 Department of Biochemistry and reticulum kinase) phosphorylates eIF2a in response to unfolded proteins in the endoplasmic Goodman Cancer Research Centre, McGill University, Montreal, QC H3A reticulum (ER) as part of the unfolded protein response (UPR) (see Glossary), while the eIF2a 1A3, Canada kinases protein kinase R (PKR), heme-regulated inhibitor (HRI), and general control nonder- 3 Howard Hughes Medical Institute, epressible 2 (GCN2) respond to double-stranded (ds)RNA, oxidative stress, and nutrient University of Colorado, Boulder, CO 80303, USA deprivation and UV, respectively. However, activation of these kinases is not always restricted to specific stimuli. For example, in addition to UV and nutrient deprivation stress, the UPR can activate GCN2 [4]. The diversity of inputs that trigger eIF2a kinase activation in general and in *Correspondence: neurons has not been fully elaborated. [email protected] (R. Parker). Trends in Molecular Medicine, June 2018, Vol. 24, No. 6 https://doi.org/10.1016/j.molmed.2018.04.001 575 © 2018 Elsevier Ltd. All rights reserved. eIF2B GTP GDP elF2–GDP TranslaƟon iniƟaƟon elFs Scanning AUG 7 AAAA m Gppp AAAA eIF2-GTP 43S preiniƟaƟon 43S–mRNA AUG 80S complex pp complex recogniƟon iniƟaƟon Met-tRNA elF1A 7 Gp m complex elF3 elF1 elF4F complex Figure 1. The Translation Initiation Pathway in Eukaryotes Comprises Several Key Steps. First, the eukaryotic initiation factor (eIF) 2B complex reloads the eIF2 complex with GTP to enable ternary complex formation. Next, the 43S preinitiation complex assembles and recruits mRNA to be translated. Scanning commences to then enable start codon recognition, and translation initiates upon formation of the 80S complex. Kina ses Figure 2. The Eukaryotic Initiation Glossary Factor (eIF) 2 Complex Is a Crucial Amyloid b (Ab) aggregates: PERK GCN2 HRI PKR Regulatory Nexus for Translation formed upon cleavage of the amyloid Initiation. The a subunit of the eIF2 com- precursor protein, amyloid b plex is phosphorylated (P) by any of four peptides are highly prone to kinases [protein kinase R-like endoplas- EIF2 EIF2 aggregation. Extracellular Ab mic reticulum kinase (PERK), general con- aggregates are implicated in γ γ trol nonderepressible 2 (GCN2), heme- Alzheimer’s disease pathogenesis. regulated inhibitor (HRI) and protein β α β α Integrated stress response (ISR): kinase R (PKR)] in response to stress, a conserved response to extrinsic and is dephosphorylated by stress- PP1C + GADD34 or CReP P and intrinsic cellular stresses that (stress induced) (constuve) induced (GADD34, growth arrest and causes global suppression of DNA damage inducible protein 34) or Phosphatases translational initiation through constitutively expressed (CReP, constitu- reversible phosphorylation of eIF2a tive reverter of eIF2a phosphorylation) and selective expression of stress- phosphatases. Phospho-eIF2a inhibits EIF2B EIF2B induced genes at the levels of γ the eIF2B complex, reducing guanine γ transcription and translation. α α exchange factor activity and limiting δ β β α δ β β α MEHMO syndrome: a rare γ γ translation initiation. ε ε syndrome defined by mental γ ε γ ε retardation, epileptic seizures, β δ β δ hypogenitalism, microcephaly, and α γ α γ obesity caused by mutations in the β α β α EIF2S3 gene, which encodes the gamma subunit of the eIF2 complex. RAN (Repeat-associated non- AUG) translation: translation of repeat expansion-containing RNAs in multiple open reading frames through Phosphorylation of eIF2a increases its affinity for the GEF eIF2B, and thereby limits the non-canonical (non-AUG) translation exchange of GDP for GTP [5]. Of note, under conditions of increased tRNA and eIF2gb levels, initiation, leading to generation of the a subunit of the eIF2 heterotrimer is unnecessary for ternary complex formation and mono-, di-, tetra-, and penta- peptides. translation in yeast [6]. Phosphorylation of eIF2a reduces the concentration of eIF2–GTP Repeat expansion diseases: a complexes, and thereby decreases bulk translation. However, mRNAs that contain upstream class of neurological disorders open reading frames (uORFs) can actually exhibit increased translation from the major ORF including Huntington disease, because the kinetics of eIF2–GTP and eIF3 reassociation with scanning ribosomes are slow myotonic dystrophy, and fragile X 576 Trends in Molecular Medicine, June 2018, Vol. 24, No. 6 Unstressed: abundant ternary complex mental retardation syndrome caused by repeat expansion mutations that Ternary complex reloads lead to pathogenic loss or gain of upstream of uORF2 AUG function. Tau oligomers: the neuronal microtubule-associated protein tau ATF4 ORF can aggregate and form intracellular 5′ tau oligomers and neurofibrillary uORF1 uORF2 tangles, histological hallmarks implicated in the pathogenesis of numerous tauopathies including uORF2 terminaƟon and Alzheimer’s disease and no ATF4 translaƟon frontotemporal dementia. Unfolded protein response (UPR): Stressed: limited ternary complex a coordinated cellular response to endoplasmic reticulum (ER) stress Ternary complex reloads that activates ATF6 (activating downstream of uORF2 AUG transcription factor 6), PERK (protein kinase R-like endoplasmic reticulum kinase), and IRE1 (inositol-requiring enzyme 1) to reprogram 5′ transcriptional and post- uORF1 uORF2 ATF4 ORF transcriptional gene regulation, ultimately to reduce cellular protein TranslaƟon iniƟates production and enhance protein on ATF4 AUG folding capacity in the ER. Vanishing White Matter Disease (VWMD): a rare fatal leukodystrophy Figure 3. Translation Initiation of Mammalian Activating Transcription Factor 4 (ATF4) mRNA Harboring caused by mutations in genes Inhibitory Upstream Open Reading Frames (uORFs) Is Enhanced During Stress when the Ternary Complex encoding any subunit of the EIF2B is Limited. Adapted, with permission, from [22]. complex. Episodic, progressive deterioration of the white matter can occur following trauma or illness. Wolcott–Rallison syndrome: a rare enough to bypass the upstream inhibitory