Exploring the IRE1 interactome: from canonical signaling functions to unexpected roles

The unfolded protein response (UPR) is a mechanism aiming at restoring endoplasmic reticulum (ER) homeostasis and is likely involved in other adaptive pathways. The UPR is transduced by three proteins acting as sensors and triggering downstream signaling pathways. Among them, IRE1α (referred to as IRE1 hereafter), an ER-resident type I transmembrane protein, exerts its function through both kinase and endoribonuclease activities, resulting in both XBP1 mRNA splicing and RNA degradation (Regulated IRE1 Dependent Decay, RIDD). An increasing number of studies have reported protein-protein interactions (PPi) as regulators of these signaling mechanisms, and additionally, driving other non-canonical functions. In this review, we deliver evolutive and structural insights on IRE1 and further describe how this protein interaction network (interactome) regulates IRE1 signaling abilities or mediates other cellular processes through catalytic-independent mechanisms. Moreover, we focus on newly discovered targets of IRE1 kinase activity and discuss potentially novel IRE1 functions based on the nature of the interactome, thereby identifying new fields to explore regarding this protein’s biological roles.