The unfolded protein response (UPR), stimulated by endoplasmic reticulum (ER) stress, can activate the innate immune system and lead to pro-inflammatory cytokines and type-I interferon (IFN) production in the absence of infection. In spite of the molecular link between ER stress and the innate sensing, the mechanisms behind this cross-talk are still unknown. Accordingly, we are interested in understanding the underlying mechanisms by which ER stress affects immune responses, specifically in human plasmacytoid dendritic cells (pDCs). A human pDC cell line derived from blastic pDCs neoplasms (CAL-1), shown to sense nucleic acids and produce type-I interferon (IFN) and tumor necrosis factor alpha (TNF-α), was used.
 To avoid the side effects of chemical ER-stress drugs, such as thapsigargin or tunicamycin, we explored the AB5 subtilase cytotoxin (SuBAB). The latter is a physiological ER stressor that promotes UPR through a specific single-site cleavage and inactivation of the ER-chaperone BiP. We showed that exposure to SubAB drives IFN expression in human pDCs by the concomitant activation of (PKR)-like endoplasmic reticulum kinase (PERK)-dependent integrated stress response (ISR) and stimulation of the stimulator of interferon genes (STING) pathway by a still undefined mechanism. We also observed a targeted degradation of the autophagy adaptor Tax1-binding protein 1 (TAX1BP1), mediated by the protein synthesis reduction. This is expected to affect the negative feedback exerted by the TAX1BP1/A20 complex on the TANK-binding kinase 1 (TBK1) pathway and lead to an amplification of STING signaling and type-I IFN production. Our work is the first demonstration that ISR induction mediates type-I IFN production and is a potential mechanism for triggering IFN-dependent autoimmunity in susceptible individuals. Ultimately, these  mechanisms shed a new light on how ER-stress-inducing toxins could contribute to the etiology of IFNdependent human autoimmune diseases upon bacterial infection.