Eukaryotic translation initiation factor 2B subunit epsilon (EIF2B5) (EIF2B5)

Eukaryotic translation initiation factor 2B subunit epsilon (EIF2B5) is the largest and catalytic subunit of the eIF2B complex, a heterodecaneric guanine nucleotide exchange factor (GEF) essential for protein synthesis (UniProt Q13144). It facilitates the exchange of GDP for GTP on eIF2, a rate-limiting step in translation initiation that is tightly regulated by the Integrated Stress Response (ISR) (NCBI Gene 1971). Mutations in EIF2B5 are a primary cause of Vanishing White Matter Disease (VWMD), a severe leukodystrophy characterized by myelin loss and neurological deterioration (PubMed 11726928). In various neurodegenerative conditions, the ISR becomes chronically activated, leading to a persistent inhibition of eIF2B and a global reduction in protein synthesis (Science 2013, 340:1154-1159). Therapeutic strategies focus on small-molecule activators, such as ISRIB and its clinical derivatives like DNL343, which stabilize the eIF2B complex and restore its GEF activity even in the presence of phosphorylated eIF2 (Denali Therapeutics, 2024). These activators aim to normalize protein synthesis and provide neuroprotection in diseases like VWMD, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's disease (Nature 2020, 585:455-459).

Other names

eIF2BepsiloneIF2B-epsilonLVWMCACHEIF2BE

Small molecule activation of the eIF2B decameric complex to promote guanine nucleotide exchange on eIF2, thereby reversing the inhibitory effects of eIF2 phosphorylation and suppressing the integrated stress response (ISR).