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The RNA helicase DDX3 promotes IFNB transcription via enhancing IRF-3/p300 holocomplex binding to the IFNB promoter.

ABSTRACT: The human DEAD-box protein 3 (DDX3) has been reported as a positive regulator and functions in the induction of type I interferon signaling. We elucidated the function of DDX3 in the positive regulation of IFNB production in non-pDC cells. We found that DDX3 regulates virus-induced activation of IFNB at the level of IRF-3. However, it does not affect conventional innate signaling, including IRF-3 phosphorylation, dimerization, or nuclear translocation of IRF-3, but has some downstream events after IRF-3 phosphorylation. Co-immunoprecipitation analyses revealed that DDX3 interacts with IRF-3 through its DNA-binding domain and promotes IRF-3-mediated IFNB promoter activation. DDX3 does not affect the formation of the IRF-3/p300/CBP complex. Instead, ChIP and EMSA assay revealed that DDX3 promotes the recruitment of IRF-3 and transcriptional co-activator p300/CBP to the IFNB promoter. The ATP binding pocket of DDX3 is involved in this association and is essential for the transcriptional activation. Taken together, our study demonstrates that DDX3 plays an important role in guiding a transcription factor complex formed by antiviral signaling to the target gene promoter.

SUBMITTER: Saikruang W

PROVIDER: S-EPMC8913847 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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The RNA helicase DDX3 promotes IFNB transcription via enhancing IRF-3/p300 holocomplex binding to the IFNB promoter.

Saikruang Wilaiporn W Ang Yan Ping Lena L Abe Hiroto H Kasumba Dacquin M DM Kato Hiroki H Fujita Takashi T

Scientific reports 20220310 1

The human DEAD-box protein 3 (DDX3) has been reported as a positive regulator and functions in the induction of type I interferon signaling. We elucidated the function of DDX3 in the positive regulation of IFNB production in non-pDC cells. We found that DDX3 regulates virus-induced activation of IFNB at the level of IRF-3. However, it does not affect conventional innate signaling, including IRF-3 phosphorylation, dimerization, or nuclear translocation of IRF-3, but has some downstream events aft ...[more]

PMID: 35273248

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Project description:Internal ribosome entry site (IRES)-driven translation is a common strategy among positive-sense, single-stranded RNA viruses for bypassing the host cell requirement of a 5' cap structure. In the current study, we identified the ribosomal protein L13 (RPL13) as a critical regulator of IRES-driven translation of foot-and-mouth disease virus (FMDV) but found that it is not essential for cellular global translation. RPL13 is also a determinant for translation and infection of Seneca Valley virus (SVV) and classical swine fever virus (CSFV), and this suggests that its function may also be conserved in unrelated IRES-containing viruses. We further showed that depletion of DEAD box helicase DDX3 disrupts binding of RPL13 to the FMDV IRES, whereas the reduction in RPL13 expression impairs the ability of DDX3 to promote IRES-driven translation directly. DDX3 cooperates with RPL13 to support the assembly of 80S ribosomes for optimal translation initiation of viral mRNA. Finally, we demonstrated that DDX3 affects the recruitment of the eukaryotic initiation factor eIF3 subunits e and j to the viral IRES. This work provides the first connection between DDX3 and eIF3e/j and recognition of the role of RPL13 in modulating viral IRES-dependent translation. This previously uncharacterized process may be involved in selective mRNA translation.IMPORTANCE Accumulating evidence has unveiled the roles of ribosomal proteins (RPs) belonging to the large 60S subunit in regulating selective translation of specific mRNAs. The translation speciﬁcity of the large-subunit RPs in this process is thought provoking, given the role they play canonically in catalyzing peptide bond formation. Here, we have identified the ribosomal protein L13 (RPL13) as a critical regulator of IRES-driven translation during FMDV infection. Our study supports a model whereby the FMDV IRESs recruit helicase DDX3 recognizing RPL13 to facilitate IRES-driven translation, with the assistance of eIF3e and eIF3j. A better understanding of these specific interactions surrounding IRES-mediated translation initiation could have important implications for the selective translation of viral mRNA and thus for the development of effective prevention of viral infection.

Dataset Information

The RNA helicase DDX3 promotes IFNB transcription via enhancing IRF-3/p300 holocomplex binding to the IFNB promoter.

Publications

The RNA helicase DDX3 promotes IFNB transcription via enhancing IRF-3/p300 holocomplex binding to the IFNB promoter.

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