The unfolded protein response (UPR) is a key adaptive pathway that controls endoplasmic reticulum (ER) homeostasis. The UPR is transduced by three ER-resident proteins acting as sensors of ER homeostasis in the lumen of this compartment and triggering select downstream signaling pathways in the cytosol and nucleus. Among them, IRE1α (referred to as IRE1 hereafter), a type I transmembrane protein, senses accumulation of improperly folded proteins in the ER lumen and transduces signals through both kinase and endoribonuclease activities in the cytosol. This mainly results in XBP1 mRNA unconventional splicing and RNA degradation (Regulated IRE1 Dependent Decay). Recently studies have also reported that IRE1-dependent protein-protein interactions (PPi) could modulate signaling, and drive additional non-canonical IRE1 functions. In the present study, we define the IRE1 signalosome based on literature and experimental approaches, as IRE1 binding partners able to alter IRE1 signaling. In particular, we explore the IRE1 in situ interactome using BioID linking the binding of direct IRE1 interacting partners to the regulation of IRE1 catalytic activity and identify novel functional connections with molecular machines involved in retrograde transport or RNA metabolism. This allows us to hypothesize on potentially novel IRE1 functions based on the nature of its interactome and its localization.