The molecular mechanism of RIG‐I activation and signaling

Thoresen, Daniel; Wang, W; Galls, Drew; Guo, Rong; Xu, Ling; Pyle, Anna Marie

doi:10.1111/imr.13022

Cited by 132 publications

(105 citation statements)

References 210 publications

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“…A) Immunoblot analysis of inputs and subcellular membrane flotation of 293T cell extracts that were mock or SenV-infected (4 h) followed by sucrose gradient fractionation, with fraction numbers indicated from the top of the gradient (1) to bottom (8). Fractionation controls, GAPDH for cytosol and Cox-I for membranes, are indicated and reveal that the membranes are localized to fraction #1.…”

Section: Resultsmentioning

confidence: 99%

“…Detection of RNA virus infection is initiated by cellular sensors such as RIG-I. RIG-I is a pattern recognition receptor that detects unique features of viral RNA that are generally absent in cellular RNA, referred to as pathogen-associated molecular patterns (PAMPs) (1). Sensing of viral RNA PAMPs triggers RIG-I activation and induces a downstream signaling cascade that ultimately results in transcriptional induction of type I and type III interferons (IFN) and the antiviral response (2, 3).…”

Section: Introductionmentioning

confidence: 99%

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Signaling from the RNA sensor RIG-I is regulated by ufmylation

Snider

Park

Murphy

et al. 2021

Preprint

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The RNA binding protein RIG-I is a key initiator of the antiviral innate immune response. The signaling that mediates the antiviral response downstream of RIG-I is transduced through the adaptor protein MAVS and results in the induction of type I and III interferons (IFN). This signal transduction occurs at endoplasmic reticulum (ER)-mitochondrial contact sites, to which RIG-I and other signaling proteins are recruited following their activation. RIG-I signaling is highly regulated to prevent aberrant activation of this pathway and dysregulated induction of IFN. Previously, we identified UFL1, the E3 ligase of the ubiquitin-like modifier conjugation system called ufmylation, UFL1, as one of the proteins recruited to membranes at ER-mitochondrial contact sites in response to RIG-I activation. Here, we show that UFL1, as well as the process of ufmylation, promote IFN induction in response to RIG-I activation. We find that following RNA virus infection, UFL1 is recruited to the membrane targeting protein 14-3-3ε, and that this complex is then recruited to activated RIG-I to promote downstream innate immune signaling. Importantly, loss of ufmylation prevents 14-3-3ε interaction with RIG-I, which abrogates the interaction of RIG-I with MAVS and thus downstream signal transduction that induces IFN. Our results define ufmylation as an integral regulatory component of the RIG-I signaling pathway and as a post-translational control for IFN induction.Significance StatementThe viral RNA sensor RIG-I initiates the antiviral innate immune response by activating a signaling cascade that induces interferon. Activation of the RIG-I signaling pathway is highly regulated to quickly mount a protective immune response while preventing dysregulation that can lead to excessive inflammation or autoimmune disorders. Here, we characterize one such mechanism of regulation. We describe that UFL1, an E3 ligase for the ubiquitin-like modifier conjugation system called ufmylation, is important to promote RIG-I signaling. Using molecular approaches, we show that ufmylation promotes RIG-I interaction with the membrane targeting protein 14-3-3ε. As such, ufmylation positively regulates RIG-I recruitment to its signaling adaptor proteins MAVS for induction of interferon in response to RNA virus infection.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Signaling from the RNA sensor RIG-I is regulated by ufmylation

Snider

Park

Murphy

et al. 2021

Preprint

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“…Retinoic acid-inducible gene I, melanoma differentiationassociated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) are the three major homologous helicases of RLRs (Wu et al, 2013;Yu et al, 2018;Thoresen et al, 2021). RIG-I and MDA5 displayed similar component structures, including caspase activation domain in N-terminal, recruitment domains (CARDs) for communicating with downstream signals, a DExD/H-box helicase domain with RNA binding and ATP hydrolysis activity, and a C-terminal domain (CTD; Yoneyama et al, 2004;Jiang et al, 2011;Kowalinski et al, 2011;Yu et al, 2018).…”

Section: Retinoic Acid-inducible Gene I-like Receptorsmentioning

confidence: 99%

“…RIG-I is expressed at a low level in non-infected cells, usually referred to as a resting state with RNA-binding and helicase domains covered by RDs (Kowalinski et al, 2011;Luo et al, 2011). Following recognition of PAMPs, RIG-I undergoes a conformational change that provides room for closer interaction with more PAMPs RNAs and begins to release the CARDs for MAVS interaction and signaling (Pichlmair et al, 2006;Peisley et al, 2013;Thoresen et al, 2021). When the complex consisting of RIG-I, MAVS, and other cytosolic proteins translocate from the cytoplasm to the associated mitochondrial membrane, RIG-I CARDs interact with the MAVS CARD to catalyze the filament formation of MAVS and then activates TBK1 and IKKε to initiate downstream signaling (Pichlmair et al, 2006;Peisley et al, 2013;Goubau et al, 2014).…”

Section: Retinoic Acid-inducible Gene I-like Receptorsmentioning

confidence: 99%

The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity

et al. 2022

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Posttranscriptional modifications have been implicated in regulation of nearly all biological aspects of cellular RNAs, from stability, translation, splicing, nuclear export to localization. Chemical modifications also have been revealed for virus derived RNAs several decades before, along with the potential of their regulatory roles in virus infection. Due to the dynamic changes of RNA modifications during virus infection, illustrating the mechanisms of RNA epigenetic regulations remains a challenge. Nevertheless, many studies have indicated that these RNA epigenetic marks may directly regulate virus infection through antiviral innate immune responses. The present review summarizes the impacts of important epigenetic marks on viral RNAs, including N6-methyladenosine (m6A), 5-methylcytidine (m5C), 2ʹ-O-methylation (2ʹ-O-Methyl), and a few uncanonical nucleotides (A-to-I editing, pseudouridine), on antiviral innate immunity and relevant signaling pathways, while highlighting the significance of antiviral innate immune responses during virus infection.

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“…The DExD/H box RNA helicases, RIG-I and melanoma differentiation-associated gene 5 (MDA5), participate in the activation of RLR signaling ( 77 , 78 ). These two molecules recognize dsRNAs from various viruses in the cytoplasm.…”

Section: Role Of Hbx In Rlr-mediated Signaling Pathwaysmentioning

confidence: 99%

Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection

et al. 2022

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As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.

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The molecular mechanism of RIG‐I activation and signaling

Cited by 132 publications

References 210 publications

Signaling from the RNA sensor RIG-I is regulated by ufmylation

Signaling from the RNA sensor RIG-I is regulated by ufmylation

The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity

Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection

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