Activating transcription factor 6 (ATF6) (ATF6)

Activating transcription factor 6 (ATF6) is a key transmembrane sensor of the unfolded protein response (UPR) located in the endoplasmic reticulum (ER) (UniProt: P18850). Upon the accumulation of misfolded proteins, ATF6 translocates to the Golgi apparatus where it undergoes proteolytic cleavage by Site-1 and Site-2 proteases (S1P/S2P) to release its active cytosolic transcription factor domain (PubMed: 27335232). This domain then enters the nucleus to upregulate genes involved in protein folding, lipid synthesis, and ER-associated degradation (ERAD) to restore homeostasis (PubMed: 27335231). Dysregulation of the ATF6 pathway is implicated in various pathologies, including protein-misfolding diseases, ischemia-reperfusion injury, and cancer, where it often promotes cell survival under stress (PubMed: 26028177). Consequently, both selective inhibitors like Ceapin-A7 and activators like AA147 are being explored as therapeutic strategies to either sensitize cancer cells to stress or protect vulnerable tissues from proteotoxic damage (PubMed: 31434674).

Other names

ATF6-alphaATF6ACyclic AMP-dependent transcription factor ATF-6 alphacAMP-dependent transcription factor ATF-6 alpha

Small molecule inhibitors like Ceapin-A7 prevent the translocation of ATF6 from the ER to the Golgi apparatus, thereby blocking its proteolytic activation (PubMed: 27335232). Pharmacological activators like AA147 selectively induce the ATF6 transcriptional program to enhance ER proteostasis without triggering the entire UPR (PubMed: 27335231).