ATF4 Gene - Activating Transcription Factor 4: Function, Mutations, and Disease

ATF4 (Activating transcription factor 4) encodes a basic leucine zipper (bZIP) transcription factor that belongs to the ATF/CREB family. It is a master regulator of the integrated stress response (ISR), induced by various cellular stresses including endoplasmic reticulum (ER) stress, amino acid deprivation, hypoxia, and oxidative stress. ATF4 controls the expression of genes involved in amino acid transport and metabolism, redox balance, autophagy, and apoptosis. It plays critical roles in bone development, hematopoiesis, and cancer progression.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Integrated stress response (ISR) - Reactome R-HSA-9634638

• Unfolded protein response (UPR) - KEGG hsa04141

• ATF4 activates genes in response to amino acid deprivation - Reactome R-HSA-9634600

• PERK-mediated signaling - Reactome R-HSA-381042

ATF4 is a 351-amino acid transcription factor with a C-terminal bZIP domain that mediates dimerization and DNA binding. It is ubiquitously expressed but tightly regulated at the translational level via upstream open reading frames (uORFs) in its mRNA. Under stress, eIF2α phosphorylation allows bypass of inhibitory uORFs, enabling ATF4 translation. Once translated, ATF4 forms homodimers or heterodimers with other bZIP proteins (e.g., C/EBPβ, NRF2) to regulate genes such as CHOP, GADD34, and ASNS. Its activity is critical for adaptation to stress, but chronic activation can trigger apoptosis.