Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 233

generated from each isoform that translocate to the nucleus (p50ATF6α and
p60ATF6β, respectively) ( Thuerauf et al., 2004 ). ATF6 also plays a role in
regulating ER volume increases in an XBP1-independent manner ( Bom-
miasamy et al., 2009 ) and potentiates cellular adaptation to chronic ER
stress ( Wu et al., 2007 ). However, in ATF6α knockout mice, decreases in the
basal expression of chaperones were not detected during either embryonic
or postnatal development ( Wu et al., 2007 ).
Interestingly, both ATF6 isoforms appear to play opposite roles in the
UPR since ATF6β is a transcriptional repressor of the ATF6α signal and,
therefore, a negative regulator of this branch of the UPR ( Thuerauf et al.,
2004 ). In contrast to ATF6β, ATF6α has a transactivation domain (TAD)
in its N-terminal region with high homology to the section VN8 of the
viral transcriptional factor VP16. This region was linked to an increase in
the transcriptional activity of ATF6α and its degradation via the ubiqui-
tin-proteasome system ( Thuerauf et al., 2002 ). In vitro DNA interaction
assays demonstrated that ATF6β binds to the consensus sequence in the
BiP/GRP78 promoter region and blocks ATF6α binding ( Thuerauf et al.,
2007 ). Previous results have shown that ATF6β knockdown cells are more
sensitive to tunicamycin-induced ER stress ( Thuerauf et al., 2004 ). During
the UPR, ATF6β levels regulate the intensity and the duration of responses
to ATF6α, as well as susceptibility to cell death ( Thuerauf et al., 2007 ).
Recently, it was determined that the ATF6β repressor effect depends on
glycosylation. Nonglycosylated ATF6β is not cleaved and is retained in the ER
membrane and, therefore, cannot function as a repressor ( Guan et al., 2009 ).
ATF6α is considered a very potent, but only transiently active transcription
factor, as the increase in its transcriptional activity in response to unfolded pro-
teins increases its own degradation by the proteasome ( Thuerauf et al., 2002 ).
The subfamily of CREB3 transcription factors associate with ATF6 and
function as sensors. These sensors are differentially expressed in different cell
types and vary in their ability to initiate stress signals. At least five bZIP tran-
scription factors related to ATF6 have been described. These are CREB3/
Luman, CREB3L1/OASIS, CREB3L2/BBF2H7, CREB3L3/CREBH
and CREB3L4/CREB4/AIbZIP/Tisp40. For more detailed information,
interested readers are referred to two excellent recently published reviews
( Asada et al., 2011 ; Chan et al., 2011 ).
Briefly, CREB3/Luman is expressed in some cell types, such as mono-
cytes and dendritic cells. The mechanism and physiological conditions that
lead to activation of this sensor are not entirely clear, but it is known to
participate in the expression of various genes involved in the ERAD, like