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.

IRE1α triggers cell death by promoting the intrinsic apoptosis pathway by interacting with a hub of diverse molecules through TNF receptor-associated factor 2 (TRAF2). TRAF2 and apoptosis signaling kinase 1 (Ask1) interact and phosphorylate the c-Jun N-terminal kinase (JNK).

Collectively, we showed that CSTMP induced apoptosis of A549 cells were through IRE1α-TRAF2-ASK1 complex-mediated ER stress, JNK activation, and mitochondrial dysfunction. These insights on this novel compound CSTMP may provide a novel anti-cancer candidate for the treatment of NSCLC.

May 7, 2024 · Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to...

Jun 6, 2018 · The IRE1α–TRAF2 complex increases IL-6 production via the association of nucleotide-binding oligomerization domain (NOD)-containing proteins 1 and 2 (NOD1 and NOD2) and receptor-interacting serine/threonine-protein kinase 2 (RIPK2).

It has been shown that TNF receptor-associated factor 2 (TRAF2) can be directly activated by IRE1α. TRAF2 is known to activate apoptosis signal-regulating kinase 1/MAP3K5 (ASK1) and its downstream target, c-Jun N terminal kinase 1 (JNK/MAPK8/SAPK1) [23,47].

TRAF2 is heavily regulated by ubiquitin signals, and many of the signaling functions of TRAF2 are mediated through its RING domain and likely its own role as an E3 ubiquitin ligase. The focus of this chapter will be on TRAF2 and TRAF5, which are closely related in both structure and function.

May 8, 2015 · Knockdown of IRE1α by siRNA dramatically abrogated CXC195-induced activation of TRAF2, ASK and JNK, formation of an IRE1α-TRAF2-ASK1 complex and caspase- and mitochondrial-dependent apoptosis in T24 cells.

May 8, 2015 · In the present study, we demonstrated that CXC195 was a potent anti-cancer agent against human UC T24 cells, and IRE1α-TRAF2-ASK1 complex-mediated ER stress and mitochondrial dysfunction might be involved in the signaling of CXC195-induced apoptosis.

Nov 29, 2022 · We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids.