The ATF6 Signaling
ATF6 is a type II transmembrane protein with an N-terminal bZip transcription factor domain. In response to ER stress, ATF6 translocate to the Golgi apparatus, where it is subjected to proteolysis by site-1 and site-2 protease and subsequently releases the transcriptionally active amino acid terminal domain to the membrane. TR [5], [8]. ATF6 too has two isoforms: ATF6α and ATF6β. These isoforms are found to be having opposite roles in UPR[8], [14]. ATF6α is a strong and rapidly degraded transcriptional activator whilst ATF6β is a weak and slowly degraded transcriptional activator[8]. Additionally, ATF6β acts as a transcriptional repressor of the ATF6α signal, thereby acting as a negative regulator of the ATF6 branch of the UPR[14], [15].
Several studies have reported results that ATF6 is a vital transcription regulator in ER stress response[16]–[19]. Wang et al.2000 identified that ATF6 directly binds on to a consensus DNA binding sequence under in vitro conditions. This site is found to be activated in ATF6 overexpression. When placed upstream of a reporter gene, this ATF6 site was activated by the ER stress response. Furthermore, they suggested that endogenous ATF6 seems to mediate ER stress response since dominant negative forms of ATF6 blocked the induction of this response[18]. ER stress-induced proteolysis is an essential step in UPR. This proteolysis of ATF is carried out by the subsequent involvement of site 1 protease (S1P) and site 2 protease (S2P). According to Yu et al. 2000, cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress suggesting that proteolysis of ATF is a crucial step in UPR[17]. Figure 3 shows a schematic model of ATF6 signaling pathway.