Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS

DOI PDF 被引用文献2件
  • Matthieu Gratia
    Immunity and Cancer Department, Institut Curie, Paris-Sciences-et-Lettres Research University, Institut National de la Santé et de la Recherche Medicale U932, Paris, France 1
  • Mathieu P. Rodero
    Institut National de la Santé et de la Recherche Médicale U1163, Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France 4
  • Cécile Conrad
    Immunity and Cancer Department, Institut Curie, Paris-Sciences-et-Lettres Research University, Institut National de la Santé et de la Recherche Medicale U932, Paris, France 1
  • Elias Bou Samra
    Institut Curie, Paris-Sciences-et-Lettres Research University, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3348, Orsay, France 2
  • Mathieu Maurin
    Immunity and Cancer Department, Institut Curie, Paris-Sciences-et-Lettres Research University, Institut National de la Santé et de la Recherche Medicale U932, Paris, France 1
  • Gillian I. Rice
    Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK 6
  • Darragh Duffy
    Immunobiology of Dendritic Cells, Institut National de la Santé et de la Recherche Médicale U1223, Institut Pasteur, Paris, France 7
  • Patrick Revy
    Institut National de la Santé et de la Recherche Médicale U1163, Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France 4
  • Florence Petit
    Clinique de Génétique, Centre Hospitalier Universitaire Lille, Hôpital Jeanne de Flandre, Lille, France 8
  • Russell C. Dale
    Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia 9
  • Yanick J. Crow
    Institut National de la Santé et de la Recherche Médicale U1163, Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France 4
  • Mounira Amor-Gueret
    Institut Curie, Paris-Sciences-et-Lettres Research University, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3348, Orsay, France 2
  • Nicolas Manel
    Immunity and Cancer Department, Institut Curie, Paris-Sciences-et-Lettres Research University, Institut National de la Santé et de la Recherche Medicale U932, Paris, France 1

抄録

<jats:p>Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-DNA inside cells poses a risk of triggering unchecked immune responses. The mechanisms limiting induction of inflammation by self-DNA are poorly understood. BLM RecQ–like helicase is essential for genome integrity and is deficient in Bloom syndrome (BS), a rare genetic disease characterized by genome instability, accumulation of micronuclei, susceptibility to cancer, and immunodeficiency. Here, we show that BLM-deficient fibroblasts show constitutive up-regulation of inflammatory interferon-stimulated gene (ISG) expression, which is mediated by the cGAS–STING–IRF3 cytosolic DNA–sensing pathway. Increased DNA damage or down-regulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BLM-deficient fibroblasts. cGAS-containing cytoplasmic micronuclei are increased in BS cells. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. These results reveal that BLM limits ISG induction, thus connecting DNA damage to cellular innate immune response, which may contribute to human pathogenesis.</jats:p>

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