The unfolded protein sensor IRE1 is essential for homeostatic dendritic cell maturation
Conventional type I dendritic cells (cDC1s) undergo homeostatic maturation upon apoptotic cell engulfment, hallmarked by the activation of the transcription factor LXRβ, which mediates cholesterol efflux and dampens interferon-stimulated gene expression. Here, we identify the unfolded protein response sensor IRE1 as an essential regulator of this process. Loss of IRE1 impairs cDC1, but not cDC2, homeostatic maturation and survival. IRE1 activation depends on apoptotic cell uptake and cholesterol influx, explaining its high basal activity in cDC1s. Rather than inducing a canonical unfolded protein response, IRE1 triggers a steady-state regulated IRE1-dependent decay program that degrades miR-92a-1, a microRNA targeting the cholesterol-efflux transporter Abcg1. Consequently, IRE1-deficient cDC1s show impaired cholesterol efflux and increased death, which can be rescued by blocking miRNA synthesis or treatment with reconstituted high-density lipoprotein. These findings establish IRE1 as a cholesterol sensor in cDC1s and reveal a parallel pathway to LXR that coordinates cholesterol homeostasis during DC maturation. While activation of the UPR sensor IRE1 is typically associated with protein folding, cDC1s show basal IRE1 activity in the absence of ER stress. Bosteels et al. uncover that this is due to their unique engulfment capacity and is critical for homeostatic maturation.
Authors
- Wilfried Le Goff (ORCID: https://orcid.org/0000-0002-7611-9644)
- Yvan Saeys (ORCID: https://orcid.org/0000-0002-0415-1506)
- Sofie Rennen (ORCID: https://orcid.org/0000-0002-2411-2045)
- Gert Van Isterdael (ORCID: https://orcid.org/0000-0001-6626-1316)
- Louis Boon (ORCID: https://orcid.org/0000-0002-0937-9171)
- Wouter Saelens (ORCID: https://orcid.org/0000-0002-7114-6248)
- Victor Bosteels (ORCID: https://orcid.org/0000-0001-8838-021X)
- Sandra Maréchal (ORCID: https://orcid.org/0000-0002-1275-3486)
- Julie Van Duyse (ORCID: https://orcid.org/0000-0001-7170-0061)
- Farzaneh Fayazpour (ORCID: https://orcid.org/0000-0001-5469-1853)
- Sven Eyckerman (ORCID: https://orcid.org/0000-0001-7525-0096)
- Annick Verhee (ORCID: https://orcid.org/0000-0003-4367-3638)
- Pieter Mestdagh (ORCID: https://orcid.org/0000-0001-7821-9684)
- Clint De Nolf (ORCID: https://orcid.org/0000-0002-2033-1830)
- Sophie Janssens (ORCID: https://orcid.org/0000-0003-1702-1636)
- Evelien Van De Velde (ORCID: https://orcid.org/0000-0003-4125-2952)
- Liesbet Martens (ORCID: https://orcid.org/0000-0001-9180-7456)
- Bart N. Lambrecht (ORCID: https://orcid.org/0000-0003-4376-6834)
- Eva Cloots (ORCID: https://orcid.org/0000-0002-8202-3905)
- Kim Deswarte (ORCID: https://orcid.org/0000-0002-9761-6973)
- Bruno De Geest
- Laurien van Heddegem
- Seraja Amstelveen
- Isabelle Guillas
- Simon J. Tavernier
- Delphine De Sutter
Institutions
- Inserm (FR)
- Ghent University Hospital (BE)
- Erasmus MC (NL)
- Ghent University (BE)
- Sorbonne Université (FR)
- VIB-UGent Center for Plant Systems Biology (BE)
- Polpharma Biologics (Netherlands) (NL)
- Cancer Research Institute Ghent (BE)
- VIB-UGent Center for Inflammation Research (BE)
- VIB-UGent Center for Medical Biotechnology (BE)
- Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR)
- Erasmus University Rotterdam (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-16
- DOI
- https://doi.org/10.1038/s41467-026-75716-z
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fonds Wetenschappelijk Onderzoek