Activating transcription factor 6 alpha (ATF6) (ATF6)

Activating transcription factor 6 alpha (ATF6) is a type II transmembrane protein located in the endoplasmic reticulum (ER) that serves as a primary sensor for the unfolded protein response (UPR) (UniProt P18850). The luminal domain of ATF6 is essential for sensing ER stress; under normal conditions, it is bound by the chaperone BiP (GRP78), which prevents its transport to the Golgi (Haze et al., 1999). When misfolded proteins accumulate, BiP dissociates, allowing ATF6 to translocate to the Golgi where it is cleaved by Site-1 and Site-2 proteases (S1P/S2P) to release its active transcription factor fragment (Ye et al., 2000). This active fragment migrates to the nucleus to induce the expression of ER chaperones and ERAD components to restore proteostasis (Adachi et al., 2008). Mutations in the ATF6 luminal domain are a known cause of achromatopsia, a hereditary visual disorder (Kohl et al., 2015). Therapeutically, the luminal domain is targeted by small molecules like Ceapins, which selectively inhibit ATF6 signaling by inducing its clustering and preventing Golgi translocation (Gallagher et al., 2016). Conversely, selective activators like AA147 target the ATF6 pathway to enhance ER folding capacity, offering potential treatments for neurodegenerative and cardiovascular diseases (Plate et al., 2016).

Other names

ATF6AATF6-alphaCyclic AMP-dependent transcription factor ATF-6 alphaProcessed cyclic AMP-dependent transcription factor ATF-6 alpha

Small molecule modulation of ATF6 ER-to-Golgi translocation and subsequent proteolytic activation to regulate the unfolded protein response.