Role of Endoplasmic Reticulum Stress Sensor IRE1α in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation

Abstract

Inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1α signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in many other diseases. Thus, further understanding of its molecular structure and mechanism of action during different cell insults helps in designing and developing better therapeutic strategies for the above-mentioned chronic diseases. In this review, recent insights into structure and mechanism of activation of IRE1α along with its complex regulating network were discussed in relation to their basic cellular physiological function. Addressing different binding partners that can modulate IRE1α function, UPRosome triggers different downstream pathways depending on the cellular backdrop. Furthermore, IRE1α are in normal cell activities outside the dominion of ER stress and activities under the weather of inflammation, diabetes, and obesity-related metaflammation. Thus, IRE1 as an ER stress sensor needs to be understood from a wider perspective for comprehensive functional meaning, which facilitates us with assembling future needs and therapeutic benefits.

Keywords: IRE1α; ROS; calcium; endoplasmic reticulum stress; insulin resistance; metaflammation; obesity; type 2 diabetes.

Figure 1

Possible mechanism of IRE1 in involvement of insulin signaling during acute and chronic Endoplasmic reticulum stress. (A) IRE1 α-XBP1s branch can generate cellular survival through increased insulin sensitivity during an acute or short-term ER stress condition. (B) However, over a long or chronic period of time, endoplasmic reticulum (ER) stress-, serine/threonine-kinase/endoribonuclease IRE1 α -binds to TNF receptor-factor 2 (TRAF2), apoptosis signaling kinase1 (ASK1), and receptor-serine/threonine protein kinase 1 (RIPK1), resulting in c-N-kinase phosphorylation this eventually triggers insulin receptor ablation and results in insulin resistance. C-Jun then interacts with c-Fos forms the active transcription factorAP-1, and increases IL-6 and TNFα production. In addition, the IRE1α/TRAF2/ASK1 complex activates the inhibitory kappa B kinase (IKK), which phosphorylates kappa B (IκB) inhibitor, leading to the release and translocation into the nucleus where cytokine expression is induced. Proteasomes then degrade the dissociated IκB. The IRE1α–TRAF2 complex increases IL-6 production through the combination of the nucleotide-oligomerization domain (NOD)-containing proteins 1 and 2 (NOD1 and NOD2) and serine/threonine-kinase 2 (RIPK2) receptor-complex. IRE1α produces splices via its RNase function—X-box-binding protein 1 (XBP1s) transcription factor induces several pro-inflammatory cytokine expression. However, XBP1s improves nuclear translocation by mediating the degradation of FoxO1, an NFκB inhibitor. In addition, the activation of IRE1α differentially controls the expression of the pro-inflammatory cytokine IL-1β gene by glycogen synthase kinase-3β activation. The controlled IRE1α-dependent decay (RIDD) degrades miR-17, resulting in increased expression of the protein that interacts with thioredoxin. This triggers the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activity, leading to procaspase-1 cleavage, which subsequently activates IL-1β and IL-18. Production of this all pro-inflammatory cytokines and inflammatory response through IRE1 either directly or indirectly leads to insulin resistance by the inhibition of insulin signaling and the activation of gluconeogenic enzymes. In addition, it may be possible to reduce the development of insulin resistance by inhibiting either small chemical molecules such as KIRA6/KIRA8, STF-083010, MKC3946, MKC8866, MKC9989, B-I09, A-I06, 4μ8C Sunitinib, Imatinib, Fortilin.