ATF6 Gene – Activating Transcription Factor 6 | Function, Mutations & Disease

ATF6 (Activating Transcription Factor 6) encodes a transcription factor that is a key mediator of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Under normal conditions, ATF6 is retained in the ER membrane bound to BiP/GRP78. Upon ER stress, ATF6 translocates to the Golgi apparatus where it is cleaved by site-1 and site-2 proteases, releasing its cytosolic N-terminal domain. This active fragment then enters the nucleus and upregulates genes involved in protein folding, ER-associated degradation (ERAD), and lipid biosynthesis. ATF6 is essential for cellular homeostasis and its dysregulation is implicated in various diseases including cancer, neurodegeneration, and metabolic disorders.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Unfolded Protein Response (UPR) – Reactome R-HSA-381119

• ATF6-alpha activates chaperones – Reactome R-HSA-381038

• ER stress and the UPR – KEGG hsa04141

ATF6 is a 670-amino acid transmembrane protein localized to the endoplasmic reticulum. It contains a basic leucine zipper (bZIP) domain in its N-terminal cytosolic region and a luminal domain that senses ER stress. Upon ER stress, ATF6 is transported to the Golgi and cleaved by S1P and S2P proteases, releasing a 50 kDa active transcription factor that translocates to the nucleus. The active form binds to ER stress response elements (ERSE) to upregulate chaperones (e.g., BiP, GRP94) and ERAD components. ATF6 is ubiquitously expressed with highest levels in retina, testis, and liver.