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.