Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells.

Autor:	Cottrell KA; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.; ICCE Institute, Washington University School of Medicine, St. Louis, Missouri.; Department of Biochemistry, Purdue University, West Lafayette, Indiana., Ryu S; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.; ICCE Institute, Washington University School of Medicine, St. Louis, Missouri., Pierce JR; Department of Biochemistry, Purdue University, West Lafayette, Indiana., Soto Torres L; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.; ICCE Institute, Washington University School of Medicine, St. Louis, Missouri., Bohlin HE; Department of Biochemistry, Purdue University, West Lafayette, Indiana., Schab AM; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.; ICCE Institute, Washington University School of Medicine, St. Louis, Missouri., Weber JD; Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.; ICCE Institute, Washington University School of Medicine, St. Louis, Missouri.; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.; Department of Biology, Siteman Cancer Center, St. Louis, Missouri.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Apr 04; Vol. 4 (4), pp. 986-1003.
DOI:	10.1158/2767-9764.CRC-23-0488
Abstrakt:	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 IFN-inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for adenosine deaminase acting on RNA 1 (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. Significance: These findings implicate DHX9 as a suppressor of dsRNA sensing. In some cell lines, loss of DHX9 alone is sufficient to cause activation of dsRNA sensing pathways, while in other cell lines DHX9 functions redundantly with ADAR1 to suppress pathway activation. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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