IRE1α Implications in Endoplasmic Reticulum Stress-Mediated Development and Pathogenesis of Autoimmune Diseases

Abstract

Inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) is the most prominent and evolutionarily conserved endoplasmic reticulum (ER) membrane protein. This transduces the signal of misfolded protein accumulation in the ER, named as ER stress, to the nucleus as “unfolded protein response (UPR).” The ER stress-mediated IRE1α signaling pathway arbitrates the yin and yang of cell life. IRE1α has been implicated in several physiological as well as pathological conditions, including immune disorders. Autoimmune diseases are caused by abnormal immune responses that develop due to genetic mutations and several environmental factors, including infections and chemicals. These factors dysregulate the cell immune reactions, such as cytokine secretion, antigen presentation, and autoantigen generation. However, the mechanisms involved, in which these factors induce the onset of autoimmune diseases, are remaining unknown. Considering that these environmental factors also induce the UPR, which is expected to have significant role in secretory cells and immune cells. The role of the major UPR molecule, IRE1α, in causing immune responses is well identified, but its role in inducing autoimmunity and the pathogenesis of autoimmune diseases has not been clearly elucidated. Hence, a better understanding of the role of IRE1α and its regulatory mechanisms in causing autoimmune diseases could help to identify and develop the appropriate therapeutic strategies. In this review, we mainly center the discussion on the molecular mechanisms of IRE1α in the pathophysiology of autoimmune diseases.

Reactive oxygen species‐mediated endoplasmic reticulum stress response induces apoptosis ofMycobacterium avium‐infected macrophages by activating regulated IRE1‐dependent decay pathway

“…Under ER stress, IRE1α is involved in virus-mediated apoptosis (Huang et al, 2016). The IRE1α activates the nuclear factor-kappa B signalling pathway (Lencer, DeLuca, Grey, & Cho, 2015) and the expression of proinflammatory cytokines in immune cells (Junjappa, Patil, Bhattarai, Kim, & Chae, 2018). A previous study has demonstrated that the RIDD pathway promotes inflammation and apoptosis via the NLRP3 inflammasome (Lerner et al, 2012).…”

Unravel the molecular mechanism of XBP1 in regulating the biology of cancer cells

“…Whether these abnormal proteins induce immunogenic effects still needed to be elucidated systematically. The roles of ER stress and its signaling pathways in immune responses have been comprehensively reviewed recently 35, 36.…”

Cistanches deserticola PhG‐RE through Inhibiting ERS Apoptosis Mechanism to Protect Myocardial Cell Apoptosis from H2O2‐Induced Endoplasmic Reticulum Stress

“…When ER stress occurs, the transcription factor CHOP can cause the release of Cyt C and apoptosis-inducing factors (AIFs), which results in cellular apoptosis [ 18 – 20 ]. Moreover, the highly conserved ER membrane protein IRE1 α can be phosphorylated and induce cell apoptosis by activating an alternative pathway through TRAF2- and apoptosis signal-regulating kinase 1 (ASK1)-mediated signal transduction [ 21 ]. Pre-treatment with PhG-RE reduced the mRNA expression of GRP78, CHOP, and Caspase-12 during ER stress in H 2 O 2 -induced cells, as well as the TG-induced mRNA expression of GRP78, JNK, and Caspase-12.…”