The C-Terminal Regulatory Domain Is the RNA 5′-Triphosphate Sensor of RIG-I

Cui, Sheng; Eisenächer, Katharina; Kirchhofer, Axel; Brzózka, Krzysztof; Lammens, Alfred; Lammens, Katja; Fujita, Takashi; Conzelmann, Karl‐Klaus; Krug, Anne; Hopfner, Karl‐Peter

doi:10.1016/j.molcel.2007.10.032

Cited by 451 publications

(529 citation statements)

References 32 publications

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“…This clearly identifies the RLRs as ssRNA sensors and further suggests that their ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself. [261][262][263] The TLR and RLR signaling pathways thus complement each other and may operate in tandem, recognizing foreign dsRNA and ssRNA in various cells; the exception is that of plasmacytoid CpG suppression and CpG methylation are ligands for endosomal TLR9, which is expressed primarily in B lymphocytes and plasmacytoid dendritic cells (pDCs). [204][205][206][207] Synthetic oligodeoxynucleotides (ODNs) expressing CpG motifs mimic the activity of bacterial DNA, and activate multiple cell types including lymphocytes, NK cells and monocytes.…”

Section: Intracellular Ssrna Sensing By Rig-i-like Receptors (Rlrs)mentioning

confidence: 99%

“…255 RIG-I is an ATPase, and the structural basis of the interactions of RNA with the C-terminal regulatory domain (CRD) has just become available. 264 RIG-I binds viral RNA in a 5'-triphosphate-dependent manner and activates the RIG-I ATPase by RNA-dependent dimerization. The crystal structure reveals a zinc-binding domain that is structurally related to GDP/GTP exchange factors of Rab-like GTPases.…”

Section: Peptidoglycan Fragment Sensing By Intracellular Nod-like Recmentioning

confidence: 99%

“…The crystal structure reveals a zinc-binding domain that is structurally related to GDP/GTP exchange factors of Rab-like GTPases. 264 A detailed characterization of the immunostimulatory and adjuvantic effects of RLR activation is yet to be established.…”

Section: Peptidoglycan Fragment Sensing By Intracellular Nod-like Recmentioning

confidence: 99%

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Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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Section: Intracellular Ssrna Sensing By Rig-i-like Receptors (Rlrs)mentioning

confidence: 99%

Section: Peptidoglycan Fragment Sensing By Intracellular Nod-like Recmentioning

confidence: 99%

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Potential adjuvantic properties of innate immune stimuli

et al. 2009

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“…We therefore conducted limited trypsin digestion analysis of purified RIG-I alone or bound to poly-U/UC or X region RNA containing 5'ppp. This approach provides an assessment of RIG-I RD displacement in response to PAMP RNA binding wherein the displaced RD of signaling- active RIG-I presents as a protected 17 kDa fragment [17][18][19] . As shown in Fig.…”

mentioning

confidence: 99%

Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Saito

Owen

Jiang

et al. 2008

Nature

672

735

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Innate immune defenses are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs) 1. Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people 2. Infection is governed by hepatic immune defenses triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals IRF-3 activation to induce the expression of α/β interferon (IFN) and antiviral/interferon-stimulated genes (ISGs) that limit infection 3 -10. Here we identified the poly-uridine motif of the HCV genome 3' nontranslated region (NTR) as the PAMP substrate of RIG-I, and show that this and similar homopoly-uridine motifs present in the genome of RNA viruses is the chief feature of RIG-I recognition and immune triggering 8. 5' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent upon homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signaling to induce a hepatic innate immune response in vivo, and triggered IFN and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by identifying homopoly-uridine motfis present in the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and define immunogenic features of the PAMP/RIG-I interaction that could be utilized as an immune adjuvant for vaccine and immunotherapy approaches.To determine the nature of the HCV PAMP RNA we conducted a functional screen to identify possible HCV PAMP RNA motifs. We assessed the ability of full length HCV genome RNA or contiguous HCV RNA segments to trigger the IFN-β promoter in transfected Huh7 cells. The full-length HCV genome RNA triggered innate immune signaling to induce the IFN-β promoter (Fig. 1a). Two regions of the HCV RNA, encoding nt 2406-3256 and nt 8872-9616, stimulated significant induction of the IFN-β promoter (Fig. 1b) with signaling activity respectively localized to nt 2406-2696 of the open reading frame and nt 9389-9619 encoding the 3' NTR (Fig.1c). Deletion of nt 9389-9619 but not nt 2408-2663 from the HCV genome significantly attenuated signaling to the IFN-β promoter (Fig 1d). PAMP motifs are typically conserved among strains of a pathogen 1 , and sequence comparison of multiple HCV genomes revealed global variability within nt 2406-3696 among virus strains but nt 9389-9616 encoded motifs of high conservation (Fig. S1) Thus, the viral 3' NTR might encode HCV PAMP motifs that trigger innate immune signaling in the host cell.The HCV 3' NTR is comprised of three regions: a variable region (VR) with potential secondary structure, a nonstructured poly-U/UC region containing polyuridine with interspersed ribocytidine, and the terminal X region containing three conserved stem-loop structures (Fig. 1e) 12 . We evaluated the ability of RNA encoding the HCV 3' NTR or each of its regions to trigger intracellular si...

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“…In the absence of a ligand, the CARDs are enveloped in other domains. Once a ligand is recognized by the CTD, RIG-I undergoes a conformational change and the CARDs are exposed [4], leading to an association with mitochondrial antiviral signaling (MAVS) through homotypic CARD-CARD interactions [5]. MAVS has an N-terminal CARD domain, a proline-rich region, and a C-terminal transmembrane (TM) domain [6].…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

Chiba

Matsumiya

Satoh

et al. 2015

Biochemical and Biophysical Research Communications

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Upon viral infection, the cytoplasmic viral sensor retinoic acid-inducible gene-I (RIG-I) recognizes viral RNA to activate antiviral signaling to induce type I interferon (IFN).RIG-I-like receptors (RLRs) activate antiviral signaling in a tissue-specific manner. The molecular mechanism underlying antiviral signaling in the respiratory system remains unclear.We studied antiviral signaling in the lower respiratory tract (LRT), which is the site of many harmful viral infections. Epithelial cells of the LRT can be roughly divided into two groups: bronchial epithelial cells (BECs) and pulmonary alveolar epithelial cells (AECs). These two cell types exhibit different phenotypes; therefore, we hypothesized that these cells may play different roles in antiviral innate immunity. We found that BECs exhibited higher antiviral activity than AECs. TNF receptor-associated factor 3 (TRAF3) has been shown to be a crucial molecule in RLR signaling. The expression levels of TRAF3 and TRAF5, which have conserved domains that are nearly identical, in the LRT were examined. We found that the bronchus exhibited the highest expression levels of TRAF3 and TRAF5 in the LRT. These findings suggest the importance of the bronchus in antiviral innate immunity in the LRT and indicate that TRAF3 and TRAF5 may contribute to RLR signaling.

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The C-Terminal Regulatory Domain Is the RNA 5′-Triphosphate Sensor of RIG-I

Cited by 451 publications

References 32 publications

Potential adjuvantic properties of innate immune stimuli

Potential adjuvantic properties of innate immune stimuli

Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

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