No abstract

The appearance of DNA in the cytosol is perceived as a danger signal that stimulates potent immune responses through cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). How cells regulate the activity of cGAS toward self-DNA and guard against potentially damaging autoinflammatory responses is a fundamental biological question. Here, we identify barrier-to-autointegration factor 1 (BAF) as a natural opponent of cGAS activity on genomic self-DNA. We show that BAF dynamically outcompetes cGAS for DNA binding, hence prohibiting the formation of DNA-cGAS complexes that are essential for enzymatic activity. Upon acute loss of nuclear membrane integrity, BAF is necessary to restrict cGAS activity on exposed DNA. Our observations reveal a safeguard mechanism, distinct from physical separation, by which cells protect themselves against aberrant immune responses toward genomic DNA.

No abstract

Interferon-l (IFN-l) plays an important role in mucosal immunity, but reliable information regarding the expression of the IFN-l receptor in individual cells is still missing. One reason for this knowledge gap is the lack of antibodies that specifically recognize the unique IFNLR1 subunit of the dimeric IFN-l receptor complex. In this study, we investigated whether a reporter mouse carrying a bacterial b-galactosidase gene inserted into the Ifnlr1 locus could be used to visualize IFN-l receptor-expressing cells in whole organs. First we confirmed that insertion of the reporter cassette inactivated the Ifnlr1 gene, and that gene function could be restored by removing the b-galactosidase insert by site-specific recombination. When whole tissues were analyzed, prominent b-galactosidase activity was confined to the intestinal tract of reporter mice. However, only the snout expressed b-galactosidase at levels high enough for reliable detection in whole tissue extracts. Interestingly, individual epithelial cells in the upper airways expressed b-galactosidase activity to variable degrees as determined by flow cytometry and histology, suggesting a remarkable heterogeneity in IFNLR1 expression levels. Taken together, our results demonstrate a surprisingly strong within-and cross-tissue heterogeneity of IFNLR1 expression that may have physiological implications.