DDX19 Inhibits Type I Interferon Production by Disrupting TBK1-IKKε-IRF3 Interactions and Promoting TBK1 and IKKε Degradation

Zhang, Kunli; Zhang, Yuanfeng; Xue, Jian; Meng, Qingchang; Li, Hongyang; Bi, Caihong; Li, Changyao; Hu, Liang; Yu, Huibin; Xiong, Tingting; Yang, Yuying; Cui, Shangjin; Bu, Zhigao; He, Xijun; Li, Jiangnan; Huang, Li; Weng, Changjiang

doi:10.1016/j.celrep.2019.01.029

Cited by 54 publications

(33 citation statements)

References 35 publications

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“…DDX proteins can also activate other proteins in the IRF pathway. Multiple DDX proteins can interact with IKKε, with DDX3 being phosphorylated by IKKε to induce IRF3 interaction with the TBK1-IKKε complex (378), and DDX19 blocking this interaction to inhibit IFN1 signaling (386). Similar control mechanisms have been demonstrated for DDX3 interacting with viral proteins.…”

Section: Evolution and Speciation Of Rig-i/mda5 And Rig-i/mda5-like Pmentioning

confidence: 99%

Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

2019

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RIG-I (Retinoic acid-inducible gene I) and MDA5 (Melanoma Differentiation-Associated protein 5), collectively known as the RIG-I-like receptors (RLRs), are key protein sensors of the pathogen-associated molecular patterns (PAMPs) in the form of viral double-stranded RNA (dsRNA) motifs to induce expression of type 1 interferons (IFN1) (IFNα and IFNβ) and other pro-inflammatory cytokines during the early stage of viral infection. While RIG-I and MDA5 share many genetic, structural and functional similarities, there is increasing evidence that they can have significantly different strategies to recognize different pathogens, PAMPs, and in different host species. This review article discusses the similarities and differences between RIG-I and MDA5 from multiple perspectives, including their structures, evolution and functional relationships with other cellular proteins, their differential mechanisms of distinguishing between host and viral dsRNAs and interactions with host and viral protein factors, and their immunogenic signaling. A comprehensive comparative analysis can help inform future studies of RIG-I and MDA5 in order to fully understand their functions in order to optimize potential therapeutic approaches targeting them.

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Section: Evolution and Speciation Of Rig-i/mda5 And Rig-i/mda5-like Pmentioning

confidence: 99%

Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

2019

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“…Many DDX helicase members play a role in innate immunity and viral infection [8,9]. DDX58 (RIG-I) recognizes viral RNA, DDX41 recognizes intracellular DNA and bacterial cyclic dinucleotides, DDX46 entraps m6A-demethylated antiviral transcripts in the nucleus, DDX19 promotes TBK1 and IKKε degradation, DDX39A alters binding and export of antiviral transcripts, and DDX3X activates the STING-IRF7-IFN-β signaling axis [10][11][12][13][14][15][16]. Other DDX helicases, such as DHX9, DHX36, DDX60, and DDX24, have also been identified as receptors for viral nucleic acids to regulate innate immunity [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity

Cai

et al. 2021

PLoS Pathog

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Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. However, its regulatory effect in antiviral innate immunity remains unclear. We found that DDX5 interacts with the N6-methyladenosine (m6A) writer METTL3 to regulate methylation of mRNA through affecting the m6A writer METTL3–METTL14 heterodimer complex. Meanwhile, DDX5 promoted the m6A modification and nuclear export of transcripts DHX58, p65, and IKKγ by binding conserved UGCUGCAG element in innate response after viral infection. Stable IKKγ and p65 transcripts underwent YTHDF2-dependent mRNA decay, whereas DHX58 translation was promoted, resulting in inhibited antiviral innate response by DDX5 via blocking the p65 pathway and activating the DHX58-TBK1 pathway after infection with RNA virus. Furthermore, we found that DDX5 suppresses antiviral innate immunity in vivo. Our findings reveal that DDX5 serves as a negative regulator of innate immunity by promoting RNA methylation of antiviral transcripts and consequently facilitating viral propagation.

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“…Loss of DDX39B has been reported to promote resistance to alkylating chemotherapy in glioblastoma cells 37 . Similarly, DDX19 impaired type I interferon production, resulting in suppression of encephalomyocarditis virus replication 38 . In this study, we discovered that DDX49 was overexpressed in lung adenocarcinoma tissues and cell lines in comparison with paracancerous tissues and normal cells.…”

Section: Discussionmentioning

confidence: 70%

“…37 Similarly, DDX19 impaired type I interferon production, resulting in suppression of encephalomyocarditis virus replication. 38 In this study, we discovered that DDX49 was overexpressed in lung adenocarcinoma tissues and cell lines in comparison with paracancerous tissues and normal cells. Knockdown of DDX49 suppressed A549 cell viability, invasion and promoted cell apoptosis.…”

Section: Discussionmentioning

confidence: 90%

LncRNA SNHG20 promoted proliferation, invasion and inhibited cell apoptosis of lung adenocarcinoma via sponging miR‐342 and upregulating DDX49

Wang

Zhu

et al. 2020

Thoracic Cancer

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Background: There is increasing evidence that long non-coding RNA (lncRNA) small nucleolar RNA host gene 20 (SNHG20) plays an important role in cancer. However, the function of SNHG20 in lung adenocarcinoma is unclear. The aim of our study was to investigate the roles of SNHG20 in lung adenocarcinoma. Methods: Real-time quantitative polymerasechain reaction (RT-qPCR) was used to calculate the expression of SNHG20, miR-342 and DEAD-box helicase 49 (DDX49). Dual luciferase reporter gene assay was applied to verify whether miR-342 binding to SNHG20 and DDX49. The expression correlation between miR-342 and SNHG20 or DDX49 was assessed using Pearson's correlation analysis. Results: SNHG20 and DDX49 were overexpressed, while miR-342 was lowly expressed in lung adenocarcinoma tissues and cell lines. Knockdown of SNHG20 suppressed cell proliferation, invasion and enhanced cell apoptosis. SNHG20 was found to directly bind to miR-342 and regulate the expression of miR-342. MiR-342 directly targeted DDX49 and the expression of miR-342 had negative connection with DDX49 in lung adenocarcinoma tissues. Knockdown of DDX49 inhibited the progression of lung adenocarcinoma. DDX49 partially restored the functions of SNHG20 in A549 cells. Conclusions: SNHG20 regulated lung adenocarcinoma cell proliferation, invasion and promoted cell apoptosis via miR-342/DDX49 axis. Our findings demonstrate that SNHG20/miR-342/DDX49 axis plays an important role in lung adenocarcinoma, providing a novel insight into the treatment of lung adenocarcinoma.

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DDX19 Inhibits Type I Interferon Production by Disrupting TBK1-IKKε-IRF3 Interactions and Promoting TBK1 and IKKε Degradation

Abstract: Highlights d DDX19 suppresses IRF3 phosphorylation d DDX19 competes with TBK1 or IKKε binding to the IAD domain of IRF3 d DDX19 recruits Lamtor2 to promote TBK1 and IKKε degradation d DDX19 inhibits type I IFN production and thus enhances viral replication

Cited by 54 publications

References 35 publications

Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

The RNA helicase DDX5 promotes viral infection via regulating N6-methyladenosine levels on the DHX58 and NFκB transcripts to dampen antiviral innate immunity

LncRNA SNHG20 promoted proliferation, invasion and inhibited cell apoptosis of lung adenocarcinoma via sponging miR‐342 and upregulating DDX49

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