The IRE1 Signaling
Class IRE1 sensor proteins have two isoforms in mammals: IRE1α and IRE1β
which both are dual kinase/ endonucleases[9], [10]. Although
IRE1α is universally expressed, IRE1β expression is limited to the
respiratory, gastrointestinal tracks, and other mucosal surfaces[9],
[11]. Upon oligomerization of IRE1, its carboxy-terminal
endoribonuclease domain gets Autophagy response activated through
autophosphorylation, which will subsequently splice out 26 bases from
cytoplasmic unspliced X- Box Binding Protein-1 (uXBP-1) mRNA. This
splicing event will lead to a shift in the open reading frame and allow
the spliced XBP1 (sXBP1) translation. sXBP1 up-regulates the expression
of several chaperones and proteins involved in ER-associated degradation
(ERAD) and lipid metabolism. Translation of sXBP1 also mediates the
expression of pro-inflammatory cytokines and autophagy response[3],
[5]–[7], [11]. Activated IRE1 can also mediate the
inflammatory pathways through inhibitor of NF-κB (IκB ) inhibition and
nuclear factor-κB (NF-κB) activation[8]. Figure 1 shows a schematic
model of IRE1 signaling pathway.