Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS

• DOI: 10.1084/jem.20181329
• Publication Date: 2019-04-01T18:55:14Z
• Authors: Matthieu Gratia; Mathieu P. Rodero; Cécile Conrad; Elias Bou Samra; Mathieu Maurin; Gillian I. Rice; Darragh Duffy; Patrick Revy; Florence Petit; Russell C. Dale; Yanick J. Crow; Mounira Amor-Gueret; Nicolas Manel
• Keywords: Male; Human Disease; [SDV]Life Sciences [q-bio]; Innate Immunity and Inflammation; 03 medical and health sciences; Cytosol; Genetics; 2',5'-Oligoadenylate Synthetase; Humans; Child; Research Articles; Adaptor Proteins, Signal Transducing; 0303 health sciences; RecQ Helicases; Genome Stability; Membrane Proteins; RNA-Binding Proteins; Fibroblasts; Phosphoproteins; Nucleotidyltransferases; Immunity, Innate; 3. Good health; Exodeoxyribonucleases; HEK293 Cells; [SDV.IMM]Life Sciences [q-bio]/Immunology; Interferon Regulatory Factor-3; Apoptosis Regulatory Proteins; Bloom Syndrome; DNA Damage; HeLa Cells

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.