The unfolded protein sensor IRE1a is essential for homeostatic dendritic cell maturation

The continuous engulfment of apoptotic cells initiates a homeostatic maturation program in conventional type I dendritic cells (cDC1s), hallmarked by the activation of the transcription factor LXRb, which mediates cholesterol efflux and dampens interferon stimulated gene expression. cDC1s are characterized by a high basal activation of the unfolded protein response (UPR) sensor IRE1, without concomitant induction of a proper UPR gene signature, a finding that has puzzled the field. Here we show that in absence of IRE1, the homeostatic maturation of cDC1s is blocked, while homeostatic maturation of cDC2s remains unaffected. IRE1 activation is strictly dependent on apoptotic cell engulfment and cholesterol influx, explaining its cDC1 subset specific activity. Stimulation of IRE1 endonuclease activity in cDC1s leads to a Regulated IRE1 Dependent Decay (RIDD) response, targeting miRNAs rather than mRNAs. This causes the degradation of miRNA-92a, which targets the cholesterol efflux transporter Abcg1 . Loss of IRE1 leads to defects in cholesterol efflux in mature cDC1s and concomitant cell death, while cDC2s do not show any defects. Blocking miRNA synthesis or enforcing cholesterol efflux by treatment with reconstituted high-density lipoproteins rescues cDC1s from cell death. These data highlight the central role of IRE1 as a sensor of cholesterol influx in the ER, extending IRE1’s function beyond its canonical role in protein folding. Furthermore, they underscore the tight control of cholesterol metabolism during cDC1 maturation, uncovering a second pathway to coordinate cholesterol efflux that acts in parallel to LXRb.