EIF2AK4

EIF2AK4, also known as GCN2, is a gene that encodes a protein kinase. This protein is a key regulator of the integrated stress response in eukaryotic cells. The integrated stress response is a cellular mechanism that helps cells cope with various stress conditions, such as nutrient deprivation, viral infection, or the accumulation of misfolded proteins.

The EIF2AK4 protein acts by phosphorylating the alpha subunit of eukaryotic initiation factor 2 (eIF2α). Phosphorylation of eIF2α leads to its inactivation, which in turn globally represses protein synthesis. However, this repression is not uniform. Under stress, the translation of specific mRNAs, particularly those containing upstream open reading frames (uORFs), is preferentially allowed. This selective translation allows the cell to synthesize proteins that are crucial for adaptation and survival during stress.

Mutations in the EIF2AK4 gene have been associated with certain human diseases. Notably, biallelic loss-of-function mutations in EIF2AK4 are a significant cause of pulmonary veno-occlusive disease (PVOD), a rare and severe disorder characterized by the obstruction of small pulmonary veins. This highlights the critical role of EIF2AK4 in maintaining vascular health, particularly in the lungs. Research into EIF2AK4 continues to shed light on its multifaceted roles in cellular homeostasis and disease pathogenesis.