Abstract
DExD/H-box helicase 9 (DHX9), or RNA helicase A (RHA), is an abundant multifunctional nuclear protein. Although it was previously reported to act as a cytosolic DNA sensor in plasmacytoid dendritic cells (pDCs), the role and molecular mechanisms of action of DHX9 in cells that are not pDCs during DNA virus infection are not clear. Here, a macrophage-specific knockout and a fibroblast-specific knockdown of DHX9 impaired antiviral innate immunity against DNA viruses, leading to increased virus replication. DHX9 enhanced NF-B–mediated transactivation in the nucleus, which required its ATPase-dependent helicase (ATPase/helicase) domain, but not the cytosolic DNA-sensing domain. In addition, DNA virus infection did not induce cytoplasmic translocation of nuclear DHX9 in macrophages and fibroblasts. Nuclear DHX9 was associated with a multiprotein complex including both NF-B p65 and RNA polymerase II (RNAPII) in chromatin containing NF-B–binding sites. DHX9 was essential for the recruitment of RNAPII rather than NF-B p65, to the corresponding promoters; this function also required its ATPase/helicase activity. Taken together, our results show a critical role of nuclear DHX9 (as a transcription coactivator) in the stimulation of NFB–mediated innate immunity against DNA virus infection, independently of DHX9’s DNA-sensing function.
Original language | English |
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Pages (from-to) | 9011-9026 |
Number of pages | 16 |
Journal | Nucleic acids research |
Volume | 46 |
Issue number | 17 |
DOIs | |
Publication status | Published - 2018 Sept 28 |
Bibliographical note
Funding Information:Korea University Grant and the National Research Foundation of Korea (NRF) funded by the Ministry of Education [2018R1A2B6001363 to M.J.S.]. Funding for open access charge: National Research Foundation of Korea (NRF) funded by the Ministry of Education [2018R1A2B6001363]. Conflict of interest statement. None declared.
Funding Information:
We thank Dr. Kathleen Boris-Lawrie (University of Minnesota, St. Paul, MN, USA) for the FLAG-DHX9 and DHX9 (K417R) constructs and Dr. Mien-Chie Hung (The University of Texas, MD Anderson Cancer Center, Houston, TX, USA) for the human DHX9 shRNA constructs. Korea University Grant and the National Research Foundation of Korea (NRF) funded by the Ministry of Education [2018R1A2B6001363 to M.J.S.]. Funding for open access charge: National Research Foundation of Korea (NRF) funded by the Ministry of Education [2018R1A2B6001363].
Publisher Copyright:
© The Author(s) 2018.
ASJC Scopus subject areas
- Genetics