Filament assemblies in foreign nucleic acid sensors

Sohn, Jungsan; Hur, Sun

doi:10.1016/j.sbi.2016.01.011

Cited by 57 publications

(66 citation statements)

References 100 publications

(74 reference statements)

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“…The autorepressed 2CARD is liberated when dsRNA binds the helicase and C-terminal domains (Hel-CTD) of RIG-I (26,27), although ATP binding was also proposed to be important (25,28). Multiple studies showed that a release of 2CARD is not sufficient for MAVS activation; it additionally requires a tetramerization of 2CARD (29). At least two non-mutually exclusive mechanisms have been proposed to stimulate 2CARD tetramerization.…”

Section: Rig-i-like Receptorsmentioning

confidence: 99%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

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291

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Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms. KeywordsdsRNA; RIG-I-like receptor; protein kinase R; oligoadenylate synthase; dsRNA-dependent adenosine deaminase; RNA interference HHS Public Access

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Section: Rig-i-like Receptorsmentioning

confidence: 99%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

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291

286

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“…Previous structural and biochemical studies have revealed a detailed picture of how RIG-I recognizes dsRNA with 5'ppp and how viral RNA binding leads to signal activation (Lassig and Hopfner, 2017;Rawling and Pyle, 2014;Sohn and Hur, 2016). In the absence of viral RNA, RIG-I is in an auto-repressed state wherein the signaling domain, the N-terminal tandem CARD (2CARD), is inhibited from activating MAVS (Kowalinski et al, 2011).…”

Section: Effective Immune Response To Viral Infection Depends On the mentioning

confidence: 99%

Ubiquitin-dependent and -independent roles of E3 ligase RIPLET in innate immunity

Cadena

Ahmad

Xavier

et al. 2018

Preprint

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The conventional view posits that E3 ligases function primarily through conjugating ubiquitin (Ub) to their substrate molecules. We report here that RIPLET, an essential E3 ligase in antiviral immunity, promotes the antiviral signaling activity of the viral RNA receptor RIG-I through both Ub-dependent and -independent manners. RIPLET uses its dimeric structure and a bivalent binding mode to preferentially recognize and ubiquitinate RIG-I pre-oligomerized on dsRNA. In addition, RIPLET can cross-bridge RIG-I filaments on longer dsRNAs, inducing aggregate-like RIG-I assemblies. The consequent receptor clustering synergizes with the Ub-dependent mechanism to amplify RIG-I-mediated antiviral signaling in an RNA-length dependent manner.These observations show the unexpected role of an E3 ligase as a co-receptor that directly participates in receptor oligomerization and ligand discrimination. It also highlights a previously unrecognized mechanism by which the innate immune system measures foreign nucleic acid length, a common criterion for self vs. non-self nucleic acid discrimination. local concentration of 2CARD (Peisley et al., 2013). Second, in addition to RIG-I filament formation, K63-linked polyubiquitin (K63-Ub n ) was also shown to promote RIG-I signaling (Jiang et al., 2012). Structural studies further showed that K63-Ub n chains bind the periphery of the core 2CARD tetramer, bridging the adjacent subunits and stabilizing its assembly . The 2CARD tetramer then acts as a helical template to nucleate the MAVS filament formation for downstream signal activation (Wu and Hur, 2015).Despite the detailed understanding of the action of K63-Ub n on RIG-I, much remains debated as to how and when Ub is placed on RIG-I, which E3 ligase is involved and how it interplays with RIG-I filament formation. Previous studies reported that TRIM25 and RIPLET (i.e. RNF135) are two essential E3 ligases important for RIG-I signaling (Gack et al., 2007;Gao et al., 2009;Oshiumi et al., 2009;Oshiumi et al., 2010). A more recent study proposed that RIPLET and TRIM25 sequentially act on RIG-I upon viral RNA engagement . That is, RIPLET first acts on the C-terminal portion of RIG-I, releasing 2CARD, which is then modified by TRIM25. However, given the previous finding that RNA binding is sufficient to release 2CARD (Kowalinski et al., 2011), it was unclear whether RIPLET indeed acts to release 2CARD and if so, how. At the same time, accumulating evidence suggested that TRIM25 has multiple, RIG-I-independent antiviral functions (Choudhury et al., 2014;Li et al., 2017;Manokaran et al., 2015;Meyerson et al., 2017;Zheng et al., 2017), raising the question whether the observed effect of TRIM25 on RIG-I represents a direct or an indirect effect.We here report a combination of cellular and biochemical data showing that RIG-I activation is dependent on RIPLET, not TRIM25, and that RIPLET suffices to ubiquitinate and activate RIG-I. In addition, RIPLET recognizes the filamentous form of RIG-I using two distinct binding modes, the interplays of which o...

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“…RIG‐I and MDA5 share a similar domain organisation. Recognition of an RNA substrate by the C‐terminal domain (CTD) of RIG‐I or MDA5 leads to structural rearrangements that are transmitted via the conserved helicase domain and allow the two N‐terminal caspase activation and recruitment domains (CARDs) to trigger oligomerisation of the adaptor MAVS (mitochondrial antiviral signalling) on the mitochondrial membrane, which in turn leads to IRF‐3, IRF‐7 and NF‐κB activation, nuclear translocation and IFN gene transcription (Goubau et al , 2013; Wu & Chen, 2014; Sohn & Hur, 2016). Whilst RIG‐I recognises 5′di‐ or tri‐phosphates at the base‐paired extremities of viral RNA, MDA5 and LGP2 recognise long double‐stranded RNA (dsRNA), the precise features of which are less well‐defined (Hornung et al , 2006; Kato et al , 2006; Pichlmair et al , 2006, 2009; Goubau et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

et al. 2018

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In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG‐I‐like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon‐stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG‐I, MDA5 and, the least‐studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus‐derived double‐stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We show that LGP2 associates with Dicer and inhibits cleavage of dsRNA into siRNAs both in vitro and in cells. Further, we show that in differentiated cells lacking components of the IFN response, ectopic expression of LGP2 interferes with RNAi‐dependent suppression of gene expression. Conversely, genetic loss of LGP2 uncovers dsRNA‐mediated RNAi albeit less strongly than complete loss of the IFN system. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs. LGP2‐mediated antagonism of dsRNA‐mediated RNAi may help ensure that viral dsRNA substrates are preserved in order to serve as targets of antiviral ISG proteins.

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Filament assemblies in foreign nucleic acid sensors

Cited by 57 publications

References 100 publications

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Ubiquitin-dependent and -independent roles of E3 ligase RIPLET in innate immunity

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

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