Inositol Requiring Enzyme 1, a metabolic sensor at the heart of dendritic cell biology

Three endoplasmic reticulum (ER) resident proteins, IRE1, PERK and ATF6 monitor the health status of the ER and initiate the unfolded protein response (UPR) to restore ER homeostasis during stress. IRE1, a conserved endonuclease, cleaves Xbp1 mRNA and generates the key transcription factor XBP1s. My lab studies the role of IRE1 in dendritic cells (DCs), antigen presenting cells that bridge innate and adaptive immune responses and are essential both for the generation of effective immunity and tolerance. We noticed that in vivo one subset of conventional DCs -cDC1s - displays constitutive IRE1 activity, in absence of a canonical UPR response. Despite strong activation of IRE1 and concomitant induction of XBP1 splicing in cDC1s, we never observed any typical XBP1-dependent gene expression and we undertook a RNA sequencing approach to retrieve a DC-specific gene signature for XBP1. To this end, we compared WT, XBP1KO and IRE1/XBP1DKO cDC1s, all isolated from the spleen. This comparison allowed us to dissect genes downregulated due to loss of XBP1 transcriptional activity versus genes downregulated due to the activation of Regulated IRE1 Dependent Decay (RIDD), a process driven by hyperactivation of IRE1 endonuclease activity in the absence of XBP1. Our analysis revealed that many genes in cDC1s appeared regulated in an IRE1 endonuclease-but not XBP1-dependent manner. Furthermore, the data point towards a novel physiological role for IRE1 in DC homeostasis and provide unique cues for IRE1 activation in DCs, which will be the main topic of this talk.