Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS

80Citations
Citations of this article
122Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

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.

Cite

CITATION STYLE

APA

Gratia, M., Rodero, M. P., Conrad, C., Samra, E. B., Maurin, M., Rice, G. I., … Manel, N. (2019). Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS. Journal of Experimental Medicine, 216(5), 1199–1213. https://doi.org/10.1084/jem.20181329

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free