Inositol-requiring enzyme 1 alpha (IRE1α)–Protein disulfide-isomerase A6 (PDIA6) protein–protein interaction interface (IRE1α–PDIA6 PPI)

The IRE1α–PDIA6 protein–protein interaction interface is a critical regulatory site within the endoplasmic reticulum (ER) that governs the duration of the unfolded protein response (UPR) (Eletto et al., 2014, Mol Cell). Inositol-requiring enzyme 1 alpha (IRE1α) is a dual-function kinase/RNase that senses ER stress, while Protein disulfide-isomerase A6 (PDIA6, also known as P5) acts as a negative regulator by binding to the IRE1α luminal domain (UniProt P17612; UniProt Q15084). This interaction facilitates the reduction of disulfide bonds within IRE1α, leading to the disassembly of IRE1α oligomers and the subsequent attenuation of its signaling activity (Grootjans et al., 2016, Front Mol Biosci). Dysregulation of this interface is implicated in various diseases, including cancers where prolonged UPR signaling supports tumor survival, and neurodegenerative disorders where impaired ER stress responses contribute to proteotoxicity. Therapeutic targeting of this PPI offers a strategy to fine-tune IRE1α activity, either by prolonging its signaling to induce apoptosis in cancer cells or by modulating its output in metabolic and inflammatory conditions. While specific clinical inhibitors for this interface are still in early-stage research, it represents a high-value target for precision medicine in ER stress-related pathologies.

Other names

IRE1-PDIA6 complexERN1-PDIA6 interactionIRE1alpha-PDIA6 interfaceP5-IRE1 interaction

Modulation of IRE1 alpha signaling duration by inhibiting or stabilizing the interaction with PDIA6, which regulates the redox-dependent attenuation of the IRE1 alpha stress response (Eletto et al., 2014).