2003. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress

Transient protein synthesis inhibition is an important protective mechanism used by cells during various stress conditions including endoplasmic reticulum (ER) stress. This response centers on the phosphorylation state of eukaryotic initiation factor (eIF)-2, which is induced by kinases like protein kinase R-like ER kinase (PERK) and GCN2 to suppress translation and is later reversed so translation resumes. GADD34 was recently identified as the factor that activates the type 1 protein serine/threonine phosphatase (PP1), which dephospho-rylates eIF-2 during cellular stresses. Our study delin-eates a negative feedback regulatory loop in which the eIF-2-controlled inhibition of protein translation leads to GADD34 induction, which promotes translational re-covery. We show that activating transcription factor-