Induction of viral mimicry upon loss of DHX9 and ADAR1 in breast cancer cells

Detection of viral double-stranded RNA (dsRNA) is an important component of innate immunity. However, many endogenous RNAs containing double-stranded regions can be misrecognized and activate innate immunity. The interferon inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for ADA...

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Bibliographic Details
Published inbioRxiv
Main Authors Cottrell, Kyle A, Ryu, Sua, Luisangely Soto Torres, Schab, Angela M, Weber, Jason D
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 31.10.2023
Subjects
Breast cancer
Cell activation
Cell death
DNA helicase
Double-stranded RNA
Innate immunity
Mimicry
Phenotypes
RNA helicase
Tumor cell lines
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Summary:Detection of viral double-stranded RNA (dsRNA) is an important component of innate immunity. However, many endogenous RNAs containing double-stranded regions can be misrecognized and activate innate immunity. The interferon inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for ADAR1 in many cancers, including breast. Although ADAR1-p150 has been well established in this role, the functions of the constitutively expressed ADAR1-p110 isoform are less understood. We used proximity labeling to identify putative ADAR1-p110 interacting proteins in breast cancer cell lines. Of the proteins identified, the RNA helicase DHX9 was of particular interest. Knockdown of DHX9 in ADAR1-dependent cell lines caused cell death and activation of the dsRNA sensor PKR. In ADAR1-independent cell lines, combined knockdown of DHX9 and ADAR1, but neither alone, caused activation of multiple dsRNA sensing pathways leading to a viral mimicry phenotype. Together, these results reveal an important role for DHX9 in suppressing dsRNA sensing by multiple pathways.Competing Interest StatementThe authors have declared no competing interest.
DOI:10.1101/2023.02.27.530307