A DNA-sensing–independent role of a nuclear RNA helicase, DHX9, in stimulation of NF-κB–mediated innate immunity against DNA virus infection

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-κB–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-κB p65 and RNA polymerase II (RNAPII) in chromatin containing NF-κB–binding sites. DHX9 was essential for the recruitment of RNAPII rather than NF-κB 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 NF-κB–mediated innate immunity against DNA virus infection, independently of DHX9’s DNA-sensing function.

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“…Dysregulation of AP-1 is hallmark of viral pathogenesis, neoplastic transformation and tumor progression (35,46). Likewise, dysregulation of dhx9/rha is associated with productive viral infection (31,37,38,45,(47)(48)(49)(50) and tumor survival (51)(52)(53)(54). The recent finding NCBP3 is essential to mount a precise antiviral response (34) posits dysfunction in a RHA-NCBP1-NCBP3 translation pathway contributes to deficient innate response.…”

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“…In particular, DHX9 is critically involved in DNA and RNA sensing [127,128]. It also interacts with MAVS and activates NFκB and TLR signaling [129,130]. Whether SM might promote DHX9 function remains to be elucidated.…”

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“…In addition, DHX9 has proviral functions based on its requirement for the replication of multiple RNA viruses [ 96 ]. DHX9 also functions as a sensor for induction of innate immune responses against PAMPs and viruses in immune cells [ 97 , 98 , 99 ]. Thus, both RNA and DNA viruses exploit DHX9 to optimize their replication.…”