BRD9 is a druggable component of interferon-stimulated gene expression and antiviral activity.
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Authors
Börold, JacobEletto, Davide
Busnadiego, Idoia
Mair, Nina K
Moritz, Eva
Schiefer, Samira
Schmidt, Nora
Petric, Philipp P
Wong, W Wei-Lynn
Schwemmle, Martin
Hale, Benjamin G
Issue Date
2021-08-16
Metadata
Show full item recordAbstract
Interferon (IFN) induction of IFN-stimulated genes (ISGs) creates a formidable protective antiviral state. However, loss of appropriate control mechanisms can result in constitutive pathogenic ISG upregulation. Here, we used genome-scale loss-of-function screening to establish genes critical for IFN-induced transcription, identifying all expected members of the JAK-STAT signaling pathway and a previously unappreciated epigenetic reader, bromodomain-containing protein 9 (BRD9), the defining subunit of non-canonical BAF (ncBAF) chromatin-remodeling complexes. Genetic knockout or small-molecule-mediated degradation of BRD9 limits IFN-induced expression of a subset of ISGs in multiple cell types and prevents IFN from exerting full antiviral activity against several RNA and DNA viruses, including influenza virus, human immunodeficiency virus (HIV1), and herpes simplex virus (HSV1). Mechanistically, BRD9 acts at the level of transcription, and its IFN-triggered proximal association with the ISG transcriptional activator, STAT2, suggests a functional localization at selected ISG promoters. Furthermore, BRD9 relies on its intact acetyl-binding bromodomain and unique ncBAF scaffolding interaction with GLTSCR1/1L to promote IFN action. Given its druggability, BRD9 is an attractive target for dampening ISG expression under certain autoinflammatory conditions.Citation
EMBO Rep. 2021 Aug 16:e52823. doi: 10.15252/embr.202152823. Epub ahead of print.Affiliation
HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.Publisher
Wiley/EMBO PressJournal
EMBO reportsPubMed ID
34397140Type
ArticleLanguage
enEISSN
1469-3178ae974a485f413a2113503eed53cd6c53
10.15252/embr.202152823
Scopus Count
The following license files are associated with this item:
- Creative Commons
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