Biology Reference
In-Depth Information
Three branches of UPR have been described: PERK, IRE1α, and acti-
vating transcription factor (ATF6). In the rest of this chapter, we will review
general aspects of the sensors and their relationship to various aspects of cell
metabolism.
3.2. ER Stress Sensors
3.2.1. IRE1 Pathway
The inositol-requiring enzyme-1 (IRE1) is the most highly conserved
branch of the UPR. It is an ER transmembrane protein that consists of an
N-terminal luminal sensor domain, a single transmembrane domain and a
C-terminal cytosolic effector region that manifests both kinase and endori-
bonuclease activity ( Walter and Ron, 2011 ). The IRE1 pathway has been
widely described by Peter Walter's group in Saccharomyces cerevisiae , who
observed that it increases the expression of ER chaperones, thereby enhanc-
ing cell viability during ER stress ( Cox et al., 1993 ). IRE1 senses unfolded
proteins in the ER lumen, which induces receptor oligomerization and
transphosphorylation within the cytosolic effector region ( Shamu and Wal-
ter, 1996 ). The cytosolic domain also exhibits site-specific endoribonuclease
activity that cleaves a small stem-loop structure from splice junctions in the
mRNA of the nuclear factor Hac1 ( Sidrauski and Walter, 1997 ; Gonza-
lez et al., 1999 ). Hac1 is a basic-leucine zipper (bZIP) transcription factor,
which binds to the promoter of UPR-regulated genes and is more resis-
tant to ubiquitin-dependent degradation when the IRE1-mediated splicing
replaces its C-terminal ( Cox and Walter, 1996 ).
Mammalian cells have two paralogs of IRE1, IRE1α and IRE1β, shar-
ing structural similarity but different functions. Under ER stress conditions,
IRE1α catalyzes the splicing of X-box-binding protein 1 (XBP1) mRNA,
the mammalian ortholog of Hac1, while IRE1β mediates the site-specific
cleavage of 28S rRNA and translational attenuation ( Tirasophon et al.,
1998 ; Iwawaki et al., 2001 ). XBP1 is not the only target of IRE1α. Sur-
prisingly, IRE1α controls its own expression by cleaving its own mRNA
( Tirasophon et al., 2000 ); another 13 mRNA candidates of IRE1α cleavage
have recently been identified ( Oikawa et al., 2010 ).
The capacity of IRE1α to sense ER stress depends on its dissocia-
tion from BiP/GRP78 and on its direct interaction with unfolded pro-
teins. These two observations are incorporated into the two-step model of
IRE1α regulation, where initial dissociation of BiP/GRP78 from IRE1α
drives oligomerization, while subsequent binding to unfolded proteins leads
to IRE1α activation ( Kimata et al., 2007 ; Pincus et al., 2010 ). A recent study
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