EIF2AK1 and viral infectious disease: ,5,6 The ISR is the primary method by which cells can adjust the protein translational dynamics in response to signaling through four kinases that are responsive to amino acid and glucose deprivation (general control non-depressible protein 2 [GCN2]), heme deficiency (heme-regulated inhibitor [HRI]), viral infection (double-stranded RNA-dependent protein kinase [PKR]), and accumulation of unfolded protein in the endoplasmic reticulum (PKR-like endoplasmic reticulum kinase [PERK]).5