ATF4 drives the ISR and is activated through numerous stresses, such as amino acid starvation by general control non-derepressible 2 (GCN2), endoplasmic reticulum (ER) stress through protein kinase RNA-like ER kinase (PERK), viral infection through protein kinase RNA-activated (PKR) and heme deprivation by heme-regulated initiation factor 2-α kinase (HRI)34. The gene discussed is EIF2AK1; the disease is viral infectious disease.