DDX1, DDX21, and DHX36 Helicases Form a Complex with the Adaptor Molecule TRIF to Sense dsRNA in Dendritic Cells

Zhang, Zhiqiang; Kim, Taeil; Bao, Manzhu; Facchinetti, Valeria; Jung, Sung Yun; Ghaffari, Amir A.; Qin, Jun; Cheng, Genhong; Liu, Yong Jun

doi:10.1016/j.immuni.2011.03.027

Cited by 319 publications

(355 citation statements)

References 53 publications

(85 reference statements)

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“…They also showed that BTV activates the IFN-␣/␤ signaling pathway in pDCs via the MyD88 adaptor, as well as by the PKR and JNK kinases. Recently, a complex of cytoplasmic helicases including DDX1 has been identified as a new dsRNA sensor that uses the TRIF pathway to induce IFN-␣/␤ synthesis in the cytosol of DCs (67). Interestingly, this complex appeared essential for IFN-␤ production in response to reovirus infection.…”

Section: Discussionmentioning

confidence: 99%

“…5A). The expression of these gene products was silenced to target the two major canonical signaling pathways involved in viral sensing (i.e., the RLR and TLR pathways) and the recently described TRIF-dependent DexD/Hbox helicases (67). As shown in Fig.…”

Section: Btv Triggers Ifn-␤ Synthesis Through a Mavs-dependent Pathwaymentioning

confidence: 99%

“…They are detected through Toll-like receptors (TLRs) and TLR-independent molecules, including the RIG-I-like receptor (RLR) family (1,4). Several PRRs that trigger innate immune responses have been identified in the Reoviridae family; these include TLR3 (2), RIG-I and MDA5 (5,57,66), PKR (15,57), and the newly described TRIF-dependent DexD/H-box helicases (67). While viral PAMPs can trigger an antiviral response in most cells of the infected host, sensing mechanisms can vary greatly from one cell type to another.…”

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confidence: 99%

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Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

Chauveau

Doceul

Lara

et al. 2012

J Virol

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Bluetongue virus (BTV), an arthropod-borne member of the Reoviridae family, is a double-stranded RNA virus that causes an economically important livestock disease that has spread across Europe in recent decades. Production of type I interferon (alpha/beta interferon [IFN-␣/␤]) has been reported in vivo and in vitro upon BTV infection. However, the cellular sensors and signaling pathways involved in this process remain unknown. Here we studied the mechanisms responsible for the production of IFN-␤ in response to BTV serotype 8. Upon BTV infection of A549 cells, expression of IFN-␤ and other proinflammatory cytokines was strongly induced at both the protein and mRNA levels. This response appeared to be dependent on virus replication, since exposure to UV-inactivated virus failed to induce IFN-␤. We also demonstrated that BTV infection activated the transcription factors IFN regulatory factor 3 and nuclear factor B. We investigated the role of several pattern recognition receptors in this response and showed that expression of IFN-␤ was greatly reduced after small-interfering-RNA-mediated knockdown of the RNA helicase encoded by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5). In contrast, silencing of MyD88, Toll-like receptor 3, or the recently described DexD/H-box helicase DDX1 sensor had no or a weak effect on IFN-␤ induction, suggesting that the RIG-I-like receptor pathway is specifically engaged for BTV sensing. Moreover, we also showed that overexpression of either RIG-I or MDA5 impaired BTV expression in infected A549 cells. Overall, this indicates that RIG-I and MDA5 can both contribute to the recognition and control of BTV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Btv Triggers Ifn-␤ Synthesis Through a Mavs-dependent Pathwaymentioning

confidence: 99%

mentioning

confidence: 99%

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Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

Chauveau

Doceul

Lara

et al. 2012

J Virol

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“…In accordance, TRIF but not MyD88 is upregulated in HTNV-infected cells [20]. The TRIF-connected DDX1-DDX21-DHX36 complex, a cytoplasmic viral sensor consisting of several RNA helicases, could also be involved in HTNV-induced HLA-I enhancement [43]. Similarly, RIG-I KD A549 cells and parental A549 cells treated with BX795, which blocks the TBK1/IKKε signaling axis [27], failed to increase HLA-I surface expression upon HTNV infection.…”

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confidence: 83%

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

et al. 2013

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Hantaviruses are emerging human pathogens. They induce an unusually strong antiviral response of human HLA class I (HLA-I) restricted CD8 + T cells that may contribute to tissue damage and hantavirus-associated disease. In this study, we analyzed possible hantaviral mechanisms that enhance the HLA-I antigen presentation machinery. Upon hantavirus infection of various human and primate cell lines, we observed transactivation of promoters controlling classical HLA molecules. Hantavirus-induced HLA-I upregulation required proteasomal activity and was associated with increased TAP expression. Intriguingly, human DCs acquired the capacity to cross-present antigen upon hantavirus infection. Furthermore, knockdown of TIR domain containing adaptor inducing IFN-β or retinoic acid inducible gene I abolished hantavirus-driven HLA-I induction. In contrast, MyD88-dependent viral sensors were not involved in HLA-I induction. Our results show that hantaviruses strongly boost the HLA-I antigen presentation machinery by mechanisms that are dependent on both retinoic acid inducible gene I and TIR domain containing adaptor inducing IFN-β.Keywords: Antigen presentation/processing · Cross-presentation/priming · Immunopathology · Infectious diseases · Innate immunity IntroductionRapidly changing ecosystems and climate facilitate the emergence of human infections with hantaviruses [1][2][3]. In Germany, increasing numbers of hantavirus-associated disease cases have been observed [4]. The enhanced health hazard emanating from pathogenic hantavirus species has been recognized by the German National Health Institute, which has recently reprioritized infecCorrespondence: Prof. Günther Schönrich e-mail: guenther.schoenrich@charite.de tious pathogens and placed hantaviruses in the highest priority group [5].Hantaviruses belong to the family Bunyaviridae and have segmented genomes [6]. The three viral RNA segments code for a nucleoprotein (N), two glycoproteins (Gn and Gc), and a RNA-dependent RNA polymerase. Hantaviruses are transmitted to humans by inhalation of virus-containing aerosols that are derived from the excreta of hantavirus-infected rodents. These natural reservoir hosts remain asymptomatic, although they are persistently infected. In striking contrast, hantaviruses are eliminated in humans at the cost of severe symptoms such as pulmonary or renal failure. Currently, no suitable vaccines or therapeutics are C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2566-2576 Antigen processing 2567 available for prevention or treatment of human hantavirus infections [7,8].Hantaviruses are not directly cytopathic for infected cells, suggesting that the antiviral immune response itself causes hantavirus-associated syndromes [9,10]. In accordance, hantaviruses trigger an unusually potent reaction of CD8 + T lymphocytes, that is devoid of regulatory T cells, and still detectable years after resolution [11][12][13][14]. Human CD8 + T cells are stimulated by HLA class I (HLA-I) molecules that prese...

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“…Identifying such a novel complex would be highly relevant to the understanding of the molecular events involved in Poly(I:C)-triggered apoptosis as TRIF is also known to interact with the dsRNA sensor helicases complex DDX1-DDX21-DHX36 15 , and with the RIGI and MDA5 adapter VISA (also known as IPS-1) 16 to signal innate immune responses.…”

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confidence: 99%

dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8

et al. 2012

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Toll-like receptor 3 (TLR3) is a pattern-recognition receptor known to initiate an innate immune response when stimulated by double-stranded RNA (dsRNA). Components of TLR3 signaling, including TIR domain-containing adapter inducing IFN-a (TRIF), have been demonstrated to contribute to dsRNA-induced cell death through caspase-8 and receptor interacting protein (RIP)1 in various human cancer cells. We provide here a detailed analysis of the caspase-8 activating machinery triggered in response to Poly(I:C) dsRNA. Engagement of TLR3 by dsRNA in both type I and type II lung cancer cells induces the formation of an atypical caspase-8-containing complex that is devoid of classical death receptors of the TNFR superfamily, but instead is physically associated to TLR3. The recruitment of caspase-8 to TLR3 requires RIP1, and is negatively modulated by cellular inhibitor of apoptosis protein (cIAP)2-TNF receptor-associated factor (TRAF)2-TNFR-associated death domain (TRADD) ubiquitin ligase complex, which regulates RIP1 ubiquitination. Intriguingly, unlike Fas-or TRAILR-dependent death signaling, caspase-8 recruitment and activation within the TLR3 death-signaling complex appears not to be stringently dependent on Fas-associated with death domain (FADD). Our findings uncover a novel aspect of the molecular mechanisms involved during apoptosis induced by the innate immune receptor TLR3 in cancer cells.

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DDX1, DDX21, and DHX36 Helicases Form a Complex with the Adaptor Molecule TRIF to Sense dsRNA in Dendritic Cells

Cited by 319 publications

References 53 publications

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

Sensing and Control of Bluetongue Virus Infection in Epithelial Cells via RIG-I and MDA5 Helicases

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8

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