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<p>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.</p>

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The unfolded protein sensor IRE1 is essential for homeostatic dendritic cell maturation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月16日

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  • Victor Bosteels,
  • Sandra Maréchal,
  • Eva Cloots,
  • Farzaneh Fayazpour,
  • Clint De Nolf,
  • Laurien Van Heddegem,
  • Simon J. Tavernier,
  • Sofie Rennen,
  • Seraja Amstelveen,
  • Liesbet Martens,
  • Evelien Van De Velde,
  • Delphine De Sutter,
  • Annick Verhee,
  • Kim Deswarte,
  • Wouter Saelens,
  • Louis Boon,
  • Julie Van Duyse,
  • Gert Van Isterdael,
  • Isabelle Guillas,
  • Yvan Saeys,
  • Bruno De Geest,
  • Sven Eyckerman,
  • Pieter Mestdagh,
  • Bart N. Lambrecht,
  • Wilfried Le Goff,
  • Sophie Janssens

摘要

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.