IRE1α Signaling Pathways Involved in Mammalian Cell Fate Determination

Abstract

A diverse array of cellular stresses can lead to accumulation of misfolded or unfolded proteins in endoplasmic reticulum (ER), which subsequently elicits ER stress. Inositol-requiring enzyme 1α (IRE1α) is the most sensitive of the three unfolded protein response (UPR) branches which are triggered to cope with ER stress in mammalian cells. IRE1α signaling is quite context-specific on account of many adaptor and modulator proteins that directly interact with it, including heat shock proteins (HSPs), RING finger protein 13 (RNF13), poly (ADP-ribose) polymerase 16 (PARP16), Bax/Bak, and Bax inhibitor-1 (BI-1). The activated IRE1α triggers different downstream pathways depending on the UPRosome formed by distinct modulator proteins. At the initial phase of ER stress, IRE1α-XBP1 axis functions as an adaptive response. While ER stress sustains or intensifies, signals shift to apoptotic responses. Furthermore, IRE1α signaling can be exploited to the development of a wide range of prevalent human diseases, with cancer the most characterized. Here we provide an overview of recent insights into the complex IRE1α signaling network which makes IRE1α an intriguing cell fate switch. Besides, the functional relevance is presented since IRE1α activation also participates in some other physiological processes beyond protein-folding status.

Apocynin protects endothelial cells from endoplasmic reticulum stress-induced apoptosis via IRE1α engagement

“…As we all know, TG induces ER stress and activates IRE1α, which further mediates pro-survival XBP1 splicing at the initial stage. However, if the adaptive UPR signaling pathways fail to rebalance ER homeostasis, IRE1α may promote several pro-apoptotic signaling pathways, including regulated IRE1α-dependent decay (RIDD) and IRE1α-TRAF2 axis [1]. In the present study, we found that the degree of XBP1 splicing, characterized by an increase in XBP1s and a decrease in XBP1u, was higher in TG-stimulated ECs with apocynin pretreatment when compared with TG stimulation alone.…”

“…These results suggested that IRE1α is involved in apocynin-mediated anti-apoptotic signals. Previously, we have reviewed that IRE1α-evoked XBP1 splicing promotes cell survival [1]. Therefore, we then detected the protein and mRNA expression levels of XBP1s.…”

“…It has been known that XBP1 was the main target of IRE1α [1]. Thus, we next detected the protein and mRNA expression levels of XBP1s in HUVECs after apocynin stimulation.…”

“…Among the three UPR branches, inositol-requiring enzyme 1α (IRE1α) is the most sensitive arm. As we have reviewed previously [1], IRE1α functions as an intriguing cell fate switch. IRE1α contains a kinase domain and an endoribonuclease (RNase) domain.…”

CHOP and IRE1α-XBP1/JNK signaling promote Newcastle Disease Virus induced apoptosis and benefit virus proliferation

“…IRE1α also activates JNK to promote apoptosis (26). Therefore, IRE1α is involved in determination of cell fate (86). Previous studies have shown that IRE1α is activated by various virus infections, and viruses have different mechanisms to regulate IRE1α, XBP1, and JNK to facilitate their own replication.…”