Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 229

suggests that IRE1α also senses changes in membrane composition. Mutant
IRE1α incapable of sensing unfolded proteins is activated by depletion of
the membrane lipid components and by deletion of genes involved in lipid
homeostasis ( Promlek et al., 2011 ). Indeed, IRE1 gene deletion confers
auxotrophy for inositol, an important component of phospholipids in yeast
cells ( Nikawa and Yamashita, 1992 ).
Other proteins also control the activation of IRE1α. Indeed, the pro-
apoptotic Bcl-2 family members Bax and Bak form a protein complex
with the cytosolic domain of IRE1α, essential for its activation ( Hetz et al.,
2006 ). Bax inhibitor 1 (BI-1), an ER-resident protein, also forms a complex
with IRE1α, decreasing its endoribonuclease activity ( Lisbona et al., 2009 ;
Madeo and Kroemer, 2009 ).
When IRE1α is activated, the luminal ER stress signal is transduced to
the cytoplasm, activating various signaling pathways. One of these pathways
is initiated by IRE1α-mediated splicing of XBP1 mRNA, which generates
a protein that differs from its unspliced protein (XBP1u) in the C-terminal
region ( Yoshida et al., 2001 ). XBP1 is a potent transactivator that regulates
genes involved in ER protein synthesis, folding, glycosylation, ERAD, redox
metabolism, autophagy, lipid biogenesis and vesicular trafficking ( Walter and
Ron, 2011 ). XBP1u does not act directly as a transcription factor, but rather
functions as negative feedback regulator of XBP1 by sequestering the pro-
tein from the nucleus and promoting its degradation by the proteasome
( Yoshida et al., 2006 ). Moreover, a hydrophobic patch in the XBP1u nascent
peptide chain recruits its mRNA (attached to the ribosome) to the ER
membrane, where it is cleaved by IRE1α to produce pXBP1s ( Yanagitani
et al., 2009 ).
IRE1α also activates JNK by recruiting the TNF receptor-associated
adapter protein TRAF2 ( Urano et al., 2000 ). This activation by ER stress
requires the presence of MAP3K, ASK1 and ASK1-interacting protein-1
(AIP1), a transducer in the ASK1-JNK signaling pathway ( Nishitoh et al.,
2002 ; Luo et al., 2008 ). JNK activation is associated with cell death ( Kim
et al., 2006 ), and also promotes survival through the activation of c-Jun
( Zhao et al., 2008 ; Fuest et al., 2011 ), increased BiP/GRP78 and GRP94
expression ( Shinkai et al., 2010 ), as well as activation of autophagy after
ER stress ( Ogata et al., 2006 ). Similar to JNK, ER stress induces activation
of NF-κB, which is mediated by IRE1 and TRAF2 ( Kaneko et al., 2003 ).
This activation of NF-κB controls the expression of manganese superoxide
dismutase (MnSOD), an antioxidant enzyme localized in the mitochondrial
matrix ( Kaneko et al., 2004 ).