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In-Depth Information
3.2.3. ATF6 Pathway and Novel-Related Sensors
There are several cAMP response element (CRE)/ATF transcriptional
factors inserted in the ER membrane regulating multiples genes associated
with the UPR. The best known of these proteins is ATF6, which, together
with PERK and IRE1, is the third major branch of the UPR.
The ATF6 transcription factor was until fairly recently considered a
member of the protein family associated with the regulation of genes with
CRE sequences (
Hai et al., 1989
). This 90 kDa protein has a bZIP domain
(
Hai et al., 1989
;
Zhu et al., 1997
) for DNA binding after homo- or het-
erodimerization (
Parker et al., 2001
). Almost 10 years after initial descrip-
tion, the transcriptional activity of ATF6 was linked for the first time to
mammalian UPR, because it was shown to bind to ER stress response ele-
ments (ERSE) in GRP promoter regions (
Yoshida et al., 1998
). ATF6 is
now known as a single-pass type 2 transmembrane ER protein that trans-
mits stress signals directly from the ER to the nucleus and thereby induces
compensatory responses (
Haze et al., 1999
,
2001
).
ATF6 has three structural domains, a luminal C-terminal, a transmem-
brane and a cytoplasmic N-terminal domain. Two isoforms of ATF6 have
been described, ATFα (90 kDa) and ATF6β/G13/CREB-RP (110 kDa).
In the luminal domain, ATF6 has Golgi localization sequences (GLS),
two in the case of the ATF6α isoform (GLS1 and GLS2) and one (GLS2)
in the case of the ATF6β isoform (
Shen et al., 2002
). Under basal con-
ditions, ATF6 is retained in the ER via interaction with the chaper-
one BiP/GRP78 and calreticulin (
Breckenridge et al., 2003
;
Shen et al.,
2005
). During ER stress conditions, ATF6 is transported on vesicles
toward the Golgi apparatus (Schindler and Schekman, 2009), where it is
sequentially cleaved by the Site-1 and then Site-2 Proteases (S1P and S2P,
respectively) (
Shen and Prywes, 2004
). These intramembrane proteases
were initially implicated in cleavage of the transcription factor steroid
regulatory element-binding protein (SREBP), involved in lipid metabo-
lism (
Ye et al., 2000
).
The N-terminal fragment of ATF6, p50ATF6, then translocates to the
nucleus where it recognizes its consensus sequences and promotes tran-
scription of UPR genes, such as the chaperones BiP/GRP78 and GRP94
(
Yamamoto et al., 2004
;
Schröder and Kaufman, 2005
;
Yamamoto et al.,
2007
), the transcription factors CHOP (
Ma et al., 2002
) and XBP1 (
Yoshida
et al., 2001
), as well as other proteins such as p58IPK/DNAJC3 (
van Hui-
zen et al., 2003
), Herp (
Kokame et al., 2001
) and SERCA (
Thuerauf et al.,
2001
). After the cleavage of ATF6α/β by S1P and S2P, two fragments are
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