The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate

Abstract

Inositol-requiring enzyme type 1 (IRE1) is a serine/threonine kinase acting as one of three branches of the Unfolded Protein Response (UPR) signaling pathway, which is activated upon endoplasmic reticulum (ER) stress conditions. It is known to be capable of inducing both pro-survival and pro-apoptotic cellular responses, which are strictly related to numerous human pathologies. Among others, IRE1 activity has been confirmed to be increased in cancer, neurodegeneration, inflammatory and metabolic disorders, which are associated with an accumulation of misfolded proteins within ER lumen and the resulting ER stress conditions. Emerging evidence suggests that genetic or pharmacological modulation of IRE1 may have a significant impact on cell viability, and thus may be a promising step forward towards development of novel therapeutic strategies. In this review, we extensively describe the structural analysis of IRE1 molecule, the molecular dynamics associated with IRE1 activation, and interconnection between it and the other branches of the UPR with regard to its potential use as a therapeutic target. Detailed knowledge of the molecular characteristics of the IRE1 protein and its activation may allow the design of specific kinase or RNase modulators that may act as drug candidates.

Endoplasmic Reticulum Stress in Diabetic Nephrology: Regulation, Pathological Role, and Therapeutic Potential

“…The RNase activity of IRE-1 increases the degradation of RNA and subsequently reduces protein synthesis. Previously, IRE-1 was shown to regulate cell survival and apoptosis [ 12 ]. Recent studies have changed this concept by demonstrating that IRE-1 directs UPR signaling and cell fate [ 13 ].…”

Inositol Requiring Enzyme (IRE), a multiplayer in sensing endoplasmic reticulum stress

“…The IRE1 gene was originally identified by complementation of a yeast mutant auxotrophic for inositol and subsequently characterized as a serine/threonine protein kinase required for myo-inositol synthesis (Nikawa and Yamashita 1992 ). Since then, IRE1α has been identified as a component of the UPR signaling pathway important for sensing and responding to ER stress in a variety of eukaryotic organisms (Chen and Brandizzi 2013 ; Grootjans et al 2016 ; Gonzalez-Quiroz et al 2020 ; Urra et al 2020 ; Li and Howell 2021 ; Siwecka et al 2021 ). In mammals, there are two homologs of IRE1, IRE1α, and IRE1β encoded by two genes, ERN1 and ERN2 , respectively ( Figure 1 ).…”

Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

“…By contrast, post-treatment of vitamin K2 resulted in a significant reduction in expression of CHOP, suggesting that vitamin K2 helped the cells to cope up with severe ER stress conditions induced by streptozotocin and menadione, and thus vitamin K2 helped to reduce neuronal cell death by a significant reduction in the expression of CHOP. In parallel with this, during prolonged ER stress, inositol-requiring kinase 1α (IRE1α) also mediates apoptosis via the TRAF2-ASK1-p38-JNK pathway [11]. We also determined the expression of p-IRE1α by immunocytochemistry, in the presence of vitamin K2.…”

“…Chronic ER stress is marked by the activation of protein kinase RNA such as ER kinase (PERK), which then activates transcription factor 6 (ATF6), resulting in the stimulation of C/EBP homologous protein-10 (CHOP) that, in turn, increases proapoptotic proteins [10]. During chronic ER stress, inositol-requiring kinase 1α (IRE1α), an evolutionarily conserved transmembrane ER protein that activates tumor necrosis factor receptor-associated factor 2 (TRAF2)-dependent proapoptotic kinases, apoptosis signal-regulating kinase 1 (ASK1), p38, and c-Jun N-terminal kinase (JNK) and causes caspase-mediated apoptosis [11]. Heightened ER stress response also results in increased oxidative stress along with autophagy dysfunction [10].…”