EIF2AK4

EIF2AK4 (Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4), also known as GCN2 (General Control Nonderepressible 2), is a protein that in humans is encoded by the EIF2AK4 gene. This enzyme plays a critical role in the cellular response to various stress conditions, such as amino acid deprivation, UV irradiation, and heat shock. It belongs to a family of kinases that phosphorylate the alpha subunit of the eukaryotic initiation factor 2 (eIF2), leading to a reduction in protein synthesis and an enhancement of gene expression to protect cells from stress.

Function

EIF2AK4 is involved in the integrated stress response (ISR) pathway. Under normal conditions, eIF2 facilitates the transfer of Met-tRNA to the ribosome, initiating protein translation. However, under stress conditions, EIF2AK4 phosphorylates eIF2α, leading to a decrease in global protein synthesis, which helps the cell conserve resources and redirect RNA translation towards stress response proteins. This mechanism is crucial for cell survival under adverse conditions.

Clinical Significance

Mutations in the EIF2AK4 gene have been associated with Pulmonary Veno-Occlusive Disease (PVOD) and Pulmonary Capillary Hemangiomatosis (PCH), rare forms of pulmonary hypertension. These conditions are characterized by the obstruction of small pulmonary veins and capillaries, leading to increased blood pressure in the pulmonary artery. Patients with mutations in EIF2AK4 typically present with more severe symptoms and have a poorer prognosis compared to those without such mutations.

Research

Research on EIF2AK4 has expanded our understanding of cellular stress responses and has implications for the development of new therapeutic strategies for treating diseases associated with protein folding and stress, such as neurodegenerative diseases, cancer, and viral infections. Inhibitors of EIF2AK4 are being explored as potential treatments for certain types of cancer, where the inhibition of stress response pathways can make cancer cells more susceptible to chemotherapy and radiation therapy.

See Also

• Eukaryotic translation initiation factor
• Protein kinase
• Pulmonary hypertension
• Stress response