TRADD Protein Is an Essential Component of the RIG-like Helicase Antiviral Pathway

Michallet, M; Meylan, Etienne; Ermolaeva, Maria A.; Vázquez, Jessica; Rebsamen, Manuele; Curran, Joseph; Poeck, Hendrik; Bscheider, Michael; Hartmann, Gunther; König, Martin; Kalinke, Ulrich; Pasparakis, Manolis; Tschopp, Jürg

doi:10.1016/j.immuni.2008.03.013

Cited by 280 publications

(238 citation statements)

References 51 publications

(71 reference statements)

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“…TRADD is implicated in TNFRI and LMP1 CTAR2 activation of NF-B, JNK, and p38 (10,12,36) and our data confirm that RIP1 is essential for LMP1-mediated IRF7 activation (20). Downstream of RIG-I, TRADD assembles FADD, RIP1, TRAF3, and TANK in complexes that induce TBK1 or IKK -mediated IRF3 and IRF7 phosphorylation (37). TRADD may have a similar role downstream of LMP1.…”

Section: Discussionsupporting

confidence: 73%

“…IRF7 and MyD88 form a death domain complex with IRAK1, which likely recruits TRAF6, TRAF3, or TRAF2 K63-linked E3 ubiquitin ligases, to activate IKK or TBK1 to phosphorylate IRF7 (22,30). Similarly, downstream of RIG-I, Cardif assembles a complex with IRF7, TRADD, TRAF3, TANK, FADD, and RIP1, and recruits TBK1 or IKK to phosphorylate IRF7 (37). The importance of IRF7 assembly on adapters that are part of kinaseactivating complexes that mediate IRF7 phosphorylation can likely be assessed by using the decoy LMP1s used here.…”

Section: Discussionmentioning

confidence: 99%

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IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

Song

Izumi

Shinners

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1), a constitutively aggregated and activated pseudoreceptor, activates IFN regulatory factor 7 (IRF7) through RIP1. We now report that the LMP1 cytoplasmic carboxyl terminal amino acids 379 -386 bound IRF7 and activated IRF7. IRF7 activation required TRAF6 and RIP1, but not TRAF2 or TRAF3. LMP1 Y384YD386, which are required for TRADD and RIP1 binding and for NF-B activation, were not required for IRF7 binding, but were required for IRF7 activation, implicating signaling through TRADD and RIP1 in IRF7 activation. Association with active LMP1 signaling complexes was also critical for IRF7 activation because (i) a dominant-negative IRF7 bound to LMP1, blocked IRF7 association and activation, but did not inhibit LMP1 induced NF-B or TBK1 or Sendai virus-mediated IFN stimulated response element activation; and (ii) two different LMP1 transmembrane domain mutants, which fail to aggregate, each bound IRF7 and prevented LMP1 from binding and activating IRF7 in the same cell, but did not prevent NF-B activation. Thus, efficient IRF7 activation required association with LMP1 CTAR2 in proximity to LMP1 CTAR2 mediated kinase activation sites. LMP1 has a 24-aa cytoplasmic N-terminus, six hydrophobic transmembrane domains (amino acids 25 to 186) and a 200-aa cytoplasmic C-terminus (amino acids 187 to 386). The transmembrane domains induce LMP1 aggregation in plasma membrane lipid rafts and barges and constitutively activate two C-terminal cytoplasm signaling domains referred to as C-terminal activation regions (CTAR) or transformation effector sites (TES) 1 and 2, which were initially defined as amino acids 187-231 and 352-386, respectively (Fig. 1A) (2-9). CTAR1 amino acids 201 to 210 engage tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) 1, 3, 2, and 5 and CTAR2 amino acids 376-386 engage TNFRassociated death domain proteins TRADD and RIP1 (4-12). Both signaling domains activate NF-B, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase, thereby altering cell gene expression, cell survival, and immune responses (13-17).LMP1 also induces and activates IFN regulatory factor 7 (IRF7) (18-20), a critical transcription factor for type 1 IFN (IFN)-mediated innate and adaptive immune responses (21-24). IRF7 is comprised of DNA binding, constitutive activation, virus activated, inhibitory, and signal response domains and is activated by serine 477 and 479 phosphorylation (25). Although IRF7 is expressed at low levels in nonstimulated cells, IRF7 is critical for type I IFN expression, particularly in plasmacytoid dendritic cells (24,26,27). Toll-like receptor activation, LMP1 expression, viral infection, and other signals that activate IRF3 and induce IFN ␤ (IFN␤), can up-regulate IRF7 expression (18, 21-24, 28, 29). IRF7 can bind and localize to MyD88 until ligand-activated Toll-like receptors 7, 8, or 9 engage MyD88 and activate IRF7, which enters the nucleus and up-regulates IFN stimulated response elements (ISREs) to activate I...

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

Song

Izumi

Shinners

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, these pathways share multiple proteins, such as TRAFs and Death domain-containing proteins (34). Thus, these proteins must be tightly regulated to prevent crosstalk, which may result in aberrant immunological consequences.…”

Section: Discussionmentioning

confidence: 99%

TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I–like receptor-mediated innate immune response

Zhou

Jia

Xue

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Innate immunity provides the first line of host defense against invading microbial pathogens. This defense involves retinoic acidinducible gene-I-like receptors that detect viral RNA and activate the mitochondrial antiviral-signaling (MAVS) protein, an adaptor protein, leading to activation of the innate antiviral immune response. The mechanisms by which the MAVS signalosome assembles on mitochondria are only partially understood. Here, we identify tripartite motif 14 (TRIM14) as a mediator in the immune response against viral infection. TRIM14 localizes to the outer membrane of mitochondria and interacts with MAVS. Upon viral infection, TRIM14 undergoes Lys-63-linked polyubiquitination at Lys-365 and recruits NF-κB essential modulator to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3 and NF-κB pathways. Knockdown of TRIM14 disrupts the association between NF-κB essential modulator and MAVS and attenuates the antiviral response. Our results indicate that TRIM14 is a component of the mitochondrial antiviral immunity that facilitates the immune response mediated by retinoic acidinducible gene-I-like receptors.A ctivation of the innate immune response involves the detection of pathogen-associated molecular patterns (PAMPs), such as microbial nucleic acids, proteins, lipids, and carbohydrates. PAMPs are recognized by cellular pattern recognition receptors (PRRs), including Toll-like receptors, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors, and C-type lectin receptors. Upon recognition, PRRs trigger a series of signaling events that lead to the induction of type I IFNs and proinflammatory cytokines (1).RLRs such as RIG-I and melanoma differentiation-associated antigen 5 (MDA5) recognize cytosolic viral RNA (2). Upon binding of RNA to the helicase domain, RIG-I or MDA5 undergoes a conformational change (3) and is recruited to the mitochondrial antiviral signaling (MAVS) adaptor. After binding of RIG-1 or MAD5, MAVS recruits various downstream molecules and further activates two kinase complexes: the noncanonical IκB kinases (IKKs) [TANK-binding kinase 1 (TBK1)/IKKi] and the canonical IKK complexes comprised of IKKα, IKK-β, and NF-κB essential modulator (NEMO) (4, 5). The TBK1/IKKi kinases phosphorylate IFN regulatory factor 3/7 (IRF3/7), which translocates to the nucleus and drives the transcription of IFNs (6). The canonical IKKs phosphorylate IκBα, resulting in the ubiquitination and proteasomal degradation of IκBα. NF-κB then is released to the nucleus and stimulates the expression of proinflammatory genes (7).MAVS-deficient mice show abolished virus-triggered induction of IFNs and increased susceptibility to viral infection (8), indicating that MAVS is essential for the innate immune response. MAVS consists of an N-terminal caspase activation and recruitment domain, a proline-rich domain, and a C-terminal transmembrane domain that targets it to the mitochondrial outer membrane (9). It has been suggested that the mitochondrial outer membrane pr...

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“…9,10 Other components have been identified as necessary for the assembly of these signaling complexes, including TRADD, FADD, MITA and GSK3b. [11][12][13][14][15] IRF3 and IRF7 are two transcription factors that bind to the interferon-stimulated response element (ISRE) that is located on the promoters of type I IFN genes. 16 IRF3 is constitutively expressed and is responsible for the initial wave of virus-induced transcription of the IFNB1 gene, whereas IRF7 is induced by viral infection and is required for sustained transcriptional activation of IFNB1 and IFNA genes at later infection time points.…”

Section: Introductionmentioning

confidence: 99%

Death-associated protein kinase 1 is an IRF3/7-interacting protein that is involved in the cellular antiviral immune response

Zhang

Shu

et al. 2014

Cell Mol Immunol

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Interferon regulatory factor (IRF) 7 has been demonstrated to be a master regulator of virus-induced type I interferon production (IFN), and it plays a central role in the innate immune response against viruses. Here, we identified death-associated protein kinase 1 (DAPK1) as an IRF7-interacting protein by tandem affinity purification (TAP). Viral infection induced DAPK1-IRF7 and DAPK1-IRF3 interactions and overexpression of DAPK1 enhanced virus-induced activation of the interferon-stimulated response element (ISRE) and IFN-b promoters and the expression of the IFNB1 gene. Knockdown of DAPK1 attenuated the induction of IFNB1 and RIG-I expression triggered by viral infection or IFN-b, and they were enhanced by viral replication. In addition, viral infection or IFN-b treatment induced the expression of DAPK1. IFN-b treatment also activated DAPK1 by decreasing its phosphorylation level at serine 308. Interestingly, the involvement of DAPK1 in virus-induced signaling was independent of its kinase activity. Therefore, our study identified DAPK1 as an important regulator of the cellular antiviral response.

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TRADD Protein Is an Essential Component of the RIG-like Helicase Antiviral Pathway

Cited by 280 publications

References 51 publications

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

IRF7 activation by Epstein–Barr virus latent membrane protein 1 requires localization at activation sites and TRAF6, but not TRAF2 or TRAF3

TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I–like receptor-mediated innate immune response

Death-associated protein kinase 1 is an IRF3/7-interacting protein that is involved in the cellular antiviral immune response

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