Regulation and function of elF2B in neurological and metabolic disorders

Abstract

Eukaryotic initiation factor 2B, eIF2B is a guanine nucleotide exchange, factor with a central role in coordinating the initiation of translation. During stress and disease, the activity of eIF2B is inhibited via the phosphorylation of its substrate eIF2 (p-eIF2α). A number of different kinases respond to various stresses leading to the phosphorylation of the alpha subunit of eIF2 and collectively this regulation is known as the Integrated Stress Response, ISR. This targeting of eIF2B allows the cell to regulate protein synthesis and reprogramme gene expression to restore homeostasis. Advances within structural biology have furthered our understanding of how eIF2B interacts with eIF2 in both the productive GEF active form and the non-productive eIF2ɑ phosphorylated form. Here, current knowledge of the role of eIF2B in the ISR is discussed within the context of normal and disease states focussing particularly on diseases such as Vanishing White Matter Disease (VWMD) and Permanent Neonatal Diabetes Mellitus (PNDM), which are directly linked to mutations in eIF2B. The role of eIF2B in synaptic plasticity and memory formation is also discussed. In addition, the cellular localisation of eIF2B is reviewed and considered along with the role of additional in vivo eIF2B binding factors and protein modifications that may play a role in modulating eIF2B activity during health and disease.

Circumventricular organ‐hypothalamic circuit endoplasmic reticulum stress drives hepatic steatosis during obesity

“…In addition, the ER chaperone glucose‐regulated peptide 78 kDa (GRP78) was similarly elevated within the SFO of mice following HFD feeding (Figure 1C,D). Given the emerging role of the protein kinase R‐like ER kinase/eukaryotic translation initiation factorα (PERK‐eIF2α) pathway in metabolic and neurological diseases [29], we also investigated whether activation of this arm of the UPR occurs in the context of obesity‐related NAFLD. Clear increases in PERK (Figure 1E,F) and phosphorylated eIF2α (Figure 1G,H) were noted in obese animals when compared with chow controls.…”

NF-κB is a critical mediator of post-mitotic senescence in oligodendrocytes and subsequent white matter loss

“…Patients suffer from cerebral white matter degeneration associated with increased numbers of NG2-glia/OPCs similar to our IKK2-CA PLP−CreERT2 model. VWMD is caused by mutations in one of the five eukaryotic translation initiation factor genes, eucaryotic initiation factor 2B (eIF2B), which are involved in protein synthesis regulation [ 81 ]. The eIF2B complex functions as guanine nucleotide exchange factor (GEF) for eIF2 and VWMD loss-of-function mutations overall show a decrease in eIF2B GEF activity leading to repression of translation similar to eIF2α phosphorylation.…”

The integrated stress response signaling during the persistent HIV infection

“…The phosphorylation of elF2α inhibits protein translation but activates only a few genes including the essential ISR downstream transcription factors ATF4, ATG5, and CHOP. 16 , 17 The latter also controls cell growth and cell death signaling during ISR. Once recruited, these factors may use a translation initiation mechanism independent of AUG start codon recognition to bind target genes, including ATF3 ( Figure 1 ).…”