The Crosslinks between the Sensor Proteins
Although the three branches of the UPR pathway have been investigated
extensively, the interconnections between these three branches are yet
to be studied more thoroughly. But it has been found that IRE1α and ATF6
pathways pose a close relationship. In attempts of analyzing the UPR
pathway using cis -acting elements and trans -acting
elements involved with genes associated with the UPR pathway, Yoshidaet al. 2000 has reported that overexpression of soluble ATF6
activates transcription of the CHOP, XBP1 genes, and ER chaperone genes
constitutively, whereas overexpression of a dominant negative mutant of
ATF6 blocks the induction by ER stress[19]. Yoshida et
al. 2001 proposed a mechanism for ER stress response activation through
ATF6, with their findings. They proposed that in response to ER stress
ATF6 initiates and induces the expression of ER chaperones and the XBP1
gene by directly binding to ER stress response elements. Then the
spliced XBP1 produced by the activation of IRE1 induces the
transcription of ER chaperons[20].
The cis -acting unfolded protein response elements (UPRE) is
playing a significant role in UPR. Yamamoto et al. 2007
demonstrated that ER stress-mediated transactivation through UPRE and
expression of some of the ER quality control proteins diminish in ATF6α
knockout cells even in the presence of XBP1. They further reported that
ATF6 cannot directly bind with UPRE to execute the UPR, suggesting that
ATF6 and XBP1 form a heterodimerized ATF6-XBP1 complex to bind with
UPREs and this complex has shown an eight-fold higher affinity to UPRE
than the XBP1 homodimer, indicating the importance of the crosstalk
between the two branches. Additionally, they demonstrated that ATF6
plays a crucial role in ER quality control process as EDEM and HRD1, two
proteins involved in the degradation branch of ER quality control, both
depend on XBP1 and ATF6[21].
Upon the induction of ER stress, splicing of XBP1 is induced. Because of
this splicing, the C-terminal region of XBP1 is switched, resulting in
the production of both unspliced and spliced mRNA forms, which will then
lead to the production of pXBP1(U) and pXBP1(S) respectively. pXBP1(S)
functions as the transcription factor with its specific C terminal
region while pXBP1(U) acts as a shuttle between the cytoplasm and the
nucleus[16], [22], [23]. The pXBP1(U) and pXBP1(S) get
together and form the pXBP1(U) - pXBP1(S) complex which is subjected to
the proteasome, because of the presence of degradation domain on the
C-terminal of pXBP1(U)[16], [24]. Furthermore, it has been
reported by Yoshida et al. 2009 that pXBP1(U) prefers to bind
with pATF6α(N), making it susceptible to the proteasome,suggesting that pXBP1(U) has a negative effect on ATF6[24].
Moreover, Tsuru et al. 2016, reported a novel mechanism that
explains the interconnection between IRE1α expression and PERK-ATF4,
under ER stress. Their experiments showed that the splicing ratio of
XBP1 mRNA in PERK knockout cells was increased by treatment with
tunicamycin but decreased thereafter, whereas PERK-expressing cells
maintained the ratio for several hours. Therefore, they suggested that
PERK affects on IRE1α -XBP1 pathway under ER stress. Additionally, they
demonstrated that the effect of PERK on the IRE1α -XBP1 pathway occurs
in a different manner to that of ATF6 on IRE1α -XBP1 pathway[25].