Eukaryotic translation initiation factor 2B complex (eIF2B) (eIF2B)

The eukaryotic translation initiation factor 2B (eIF2B) complex is a critical decameric enzyme that functions as the guanine nucleotide exchange factor (GEF) for eIF2 (UniProt, 2024). It catalyzes the exchange of GDP for GTP on eIF2, a rate-limiting step essential for the initiation of mRNA translation and global protein synthesis (Wong et al., 2018). Under cellular stress, the alpha subunit of eIF2 is phosphorylated, converting eIF2 from a substrate into a competitive inhibitor of eIF2B, which triggers the Integrated Stress Response (ISR) and reduces protein synthesis (Sidrauski et al., 2013). Genetic mutations in eIF2B subunits are the primary cause of Vanishing White Matter Disease (VWMD), while chronic ISR activation via eIF2B inhibition is implicated in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) (PubMed, 2023). Therapeutic strategies focus on small molecule activators, such as ISRIB and DNL343, which bind to and stabilize the eIF2B complex to restore its GEF activity even in the presence of stress-induced inhibition (Denali Therapeutics, 2024). These drugs aim to alleviate the pathological effects of chronic ISR activation and are currently being evaluated in clinical trials for neurodegenerative disorders (ClinicalTrials.gov, 2024).

Other names

eIF2BGuanine nucleotide exchange factor for eIF2Eukaryotic translation initiation factor 2BeIF2B alpha/beta/gamma/delta/epsilon complex

Small molecule activators bind to the eIF2B complex to stabilize its decameric form and enhance its guanine nucleotide exchange factor (GEF) activity, thereby overcoming the inhibitory effects of phosphorylated eIF2 alpha and restoring protein synthesis while suppressing the Integrated Stress Response (ISR).