Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2 alpha (eIF2 alpha) in response to a stress signal from the endoplasmic reticulum (ER)(1,2). Activation of this process leads to reduced rates of initiation of protein translation during ER stress(3). Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Irel, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2 alpha kinases, PKR and HRI. ER stress increases PERK＇s protein-kinase activity and PERK phosphorylates eIF2 alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.