Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6) (ATF6)

Activating transcription factor 6 (ATF6) is a type II transmembrane protein residing in the endoplasmic reticulum (ER) that functions as a key sensor for the unfolded protein response (UPR) (UniProt P18850). Under conditions of ER stress, ATF6 translocates to the Golgi apparatus where it is cleaved by site-1 and site-2 proteases (S1P/S2P) to release its active N-terminal transcription factor domain (p50) (PubMed: 10564661). This fragment enters the nucleus to upregulate genes involved in protein folding, such as BiP/GRP78, and ER-associated degradation (ERAD) to restore cellular homeostasis (PubMed: 22664304). ATF6 signaling is implicated in various pathologies; for instance, its overactivation supports tumor survival and chemoresistance in several cancers, while mutations in the ATF6 gene are a known cause of achromatopsia (PubMed: 26028297). In the context of neurodegeneration, ATF6 activity is often impaired, leading to the accumulation of toxic protein aggregates (PubMed: 29233864). Pharmacological modulation of ATF6 is an emerging therapeutic area, with selective inhibitors like Ceapins being explored to block its translocation and sensitize cancer cells, and activators like AA147 being investigated to treat protein misfolding diseases by enhancing ER proteostasis (PubMed: 30108118, PubMed: 28641459).

Other names

Activating transcription factor 6 alphaATF6-alphaATF6AProcessed cyclic AMP-dependent transcription factor ATF-6 alpha

Modulation of the ATF6 pathway involves either the inhibition of ATF6 translocation from the endoplasmic reticulum to the Golgi apparatus to prevent its proteolytic activation, or the small-molecule activation of its transcriptional program to enhance the cell's protein folding capacity.