Toll-Like Receptors and RNA Helicases: Two Parallel Ways to Trigger Antiviral Responses

Meylan, Etienne; Tschopp, Jürg

doi:10.1016/j.molcel.2006.05.012

Cited by 342 publications

(298 citation statements)

References 101 publications

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“…These receptors include the toll-like receptors, the antiviral cytoplasmic helicases (RIG-I and MDA5) or NOD-like receptors, which are specialized microbial and viral sensors. 20,21 Once activated, innate receptors regulate type I interferon (IFN) and nuclear factor-kB-dependent gene expression, or process cytokines such as pro-interleukin (IL)-1b to their active and secreted forms. AAV vectors do not appear to engage pattern recognition receptors such as toll-like receptors, 22 fail to induce type I IFN responses 23 and do not induce IL-1b processing (Zaiss and Muruve, unpublished observations).…”

Section: Innate Immunitymentioning

confidence: 99%

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

2008

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Section: Innate Immunitymentioning

confidence: 99%

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

2008

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“…Activation through these innate receptors differs from that achieved via BCR signaling in several ways. First, whereas BCRs are highly diverse and interact individually with a narrow range of epitopes, TLRs bind broadly expressed, conserved molecular patterns on microbial pathogens (28). Second, whereas BCR cross-linking requires concomitant T cell help to afford optimal activation, TLR ligation per se can provide the signals required for proliferation and differentiation to Ab secretion (29).…”

Section: Tlr Stimulation Modifies Blys Receptor Expression Inmentioning

confidence: 99%

TLR Stimulation Modifies BLyS Receptor Expression in Follicular and Marginal Zone B Cells

Treml

Carlesso

Hoek

et al. 2007

The Journal of Immunology

147

133

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Through their differential interactions with B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), the three BLyS family receptors play central roles in B cell survival and differentiation. Recent evidence indicates BLyS receptor levels shift following BCR ligation, suggesting that activation cues can alter overall BLyS receptor profiles and thus ligand sensitivity. In this study, we show that TLR stimuli also alter BLyS receptor expression, but in contrast to BCR ligation, TLR9 and TLR4 signals, preferentially increase transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) expression. Although both of these TLRs act through MyD88-dependent mechanisms to increase TACI expression, they differ in terms of their downstream mediators and the B cell subset affected. Surprisingly, only TLR4 relies on c-Rel and p50 to augment TACI expression, whereas TLR9 does not. Furthermore, although all follicular and marginal zone B cells up-regulate TACI in response to TLR9 stimulation, only marginal zone B cells and a subset of follicular B cells respond to TLR4. Finally, we find that both BLyS and APRIL enhance viability among quiescent and BCR-stimulated B cells. However, although BLyS enhances viability among TLR stimulated B cells, APRIL does not, suggesting that TACI but not BLyS receptor 3 may share survival promoting pathways with TLRs.

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NLRX1 is a regulator of mitochondrial antiviral immunity

Moore

Bergstralh

Duncan

et al. 2008

Nature

510

530

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The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection [1][2][3][4][5][6] . MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)-and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH-and MAVS-mediated interferon-b promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.Mammalian members of the nucleotide-binding domain (NBD) and leucine-rich-repeat-containing (LRR) (known as NLR, see http://www.genenames.org/genefamily/nacht.html) family of proteins are indispensable for cellular responses to pathogens. This NBD-LRR protein structure is ancient and highly conserved, as shown by its initial identification among plant disease-resistance proteins 7-12 . Current dogma posits that NLRs function as cytoplasmic surveillance molecules that sense intracellular pathogen-associated molecular patterns (PAMPs), or as regulators of pathogen-initiated signalling cascades 13,14 . Viral PAMPs are detected by the cytoplasmic RLH receptors RIG-I (also known as DDX58) and MDA-5 (also known as IFIH1), which signal through the mitochondrial protein MAVS, resulting in the activation of interferon regulatory factor 3 (IRF3) and NF-kB and type-1 interferon transcription [1][2][3][4][5][6] . Abrogation of MAVS expression or function leads to reduced type 1 interferon production and antiviral protection 15 .To study the potential role of NLR proteins in regulating mitochondrial antiviral signalling, we used bioinformatics to identify NLRs localized to the mitochondria. We identified one putative mitochondrial NLR called NLRX1 (previously known as CLR11.3 and NOD9) 9,16 (Fig. 1a). The predicted peptide sequence and distinct domains of NLRX1 are shown in Supplementary Fig. 1. Consistent with the conserved motif structure of the NLR family, NLRX1 contains a central putative NBD and carboxy-terminal LRRs. The assignment of the amino-terminal effector domain to a subclass i...

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Toll-Like Receptors and RNA Helicases: Two Parallel Ways to Trigger Antiviral Responses

Cited by 342 publications

References 101 publications

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

TLR Stimulation Modifies BLyS Receptor Expression in Follicular and Marginal Zone B Cells

NLRX1 is a regulator of mitochondrial antiviral immunity

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