scholarly journals Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Charlotte Lässig ◽  
Katja Lammens ◽  
Jacob Lucián Gorenflos López ◽  
Sebastian Michalski ◽  
Olga Fettscher ◽  
...  
Keyword(s):  
Immune Response ◽  
Retinoic Acid ◽  
Rna Binding ◽  
Atp Hydrolysis ◽  
Innate Immune ◽  
Rna Recognition ◽  
Double Stranded Rna ◽  
Lower Affinity ◽  
Structural Conformation ◽  
Inducible Gene

The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (<xref ref-type="bibr" rid="bib19">Lässig et al., 2015</xref>), revealing how ATP turnover helps RIG-I distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.

scholarly journals Astrogliosis involves activation of retinoic acid-inducible gene-like signaling in the innate immune response after spinal cord injury

Glia ◽  
2011 ◽  
Vol 60 (3) ◽  
pp. 414-421 ◽  
Author(s):  
Juan Pablo de Rivero Vaccari ◽  
Julia Minkiewicz ◽  
Xiaoliang Wang ◽  
Juan Carlos De Rivero Vaccari ◽  
Ramon German ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Immune Response ◽  
Retinoic Acid ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Cord Injury ◽  
Inducible Gene

scholarly journals MAVS Coordination of Antiviral Innate Immunity

2015 ◽  
Vol 89 (14) ◽  
pp. 6974-6977 ◽  
Author(s):  
Christine Vazquez ◽  
Stacy M. Horner
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Endoplasmic Reticulum ◽  
Retinoic Acid ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Antiviral Signaling ◽  
Antiviral Innate Immunity ◽  
Inducible Gene

RNA virus infection is sensed in the cytoplasm by the retinoic acid-inducible gene I (RIG-I)-like receptors. These proteins signal through the host adaptor protein MAVS to trigger the antiviral innate immune response. Here, we describe how MAVS subcellular localization impacts its function and the regulation underlying MAVS signaling. We propose a model to describe how the coordination of MAVS functions at the interface between the mitochondria and the mitochondrion-associated endoplasmic reticulum (ER) membrane programs antiviral signaling.

scholarly journals LGP2 binds to PACT to regulate RIG-I– and MDA5-mediated antiviral responses

2019 ◽  
Vol 12 (601) ◽  
pp. eaar3993 ◽  
Author(s):  
Raul Y. Sanchez David ◽  
Chantal Combredet ◽  
Valérie Najburg ◽  
Gael A. Millot ◽  
Guillaume Beauclair ◽  
...  
Keyword(s):  
Rna Silencing ◽  
Rna Binding ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Type I ◽  
Double Stranded Rna ◽  
Rna Molecules ◽  
Protein Protein Interaction ◽  
Antiviral Responses ◽  
Inducible Gene

The retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs) RIG-I, MDA5, and LGP2 stimulate inflammatory and antiviral responses by sensing nonself RNA molecules produced during viral replication. Here, we investigated how LGP2 regulates the RIG-I– and MDA5-dependent induction of type I interferon (IFN) signaling and showed that LGP2 interacted with different components of the RNA-silencing machinery. We identified a direct protein-protein interaction between LGP2 and the IFN-inducible, double-stranded RNA binding protein PACT. The LGP2-PACT interaction was mediated by the regulatory C-terminal domain of LGP2 and was necessary for inhibiting RIG-I–dependent responses and for amplifying MDA5-dependent responses. We described a point mutation within LGP2 that disrupted the LGP2-PACT interaction and led to the loss of LGP2-mediated regulation of RIG-I and MDA5 signaling. These results suggest a model in which the LGP2-PACT interaction regulates the inflammatory responses mediated by RIG-I and MDA5 and enables the cellular RNA-silencing machinery to coordinate with the innate immune response.

scholarly journals Establishing the role of ATP for the function of the RIG-I innate immune sensor

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
David C Rawling ◽  
Megan E Fitzgerald ◽  
Anna Marie Pyle
Keyword(s):  
Immune Response ◽  
Atp Hydrolysis ◽  
Innate Immune ◽  
Atp Binding ◽  
Rna Molecules ◽  
Proof Reading ◽  
Atp Binding And Hydrolysis ◽  
Signal Activation ◽  
Inducible Gene

Retinoic acid-inducible gene I (RIG-I) initiates a rapid innate immune response upon detection and binding to viral ribonucleic acid (RNA). This signal activation occurs only when pathogenic RNA is identified, despite the ability of RIG-I to bind endogenous RNA while surveying the cytoplasm. Here we show that ATP binding and hydrolysis by RIG-I play a key role in the identification of viral targets and the activation of signaling. Using biochemical and cell-based assays together with mutagenesis, we show that ATP binding, and not hydrolysis, is required for RIG-I signaling on viral RNA. However, we show that ATP hydrolysis does provide an important function by recycling RIG-I and promoting its dissociation from non-pathogenic RNA. This activity provides a valuable proof-reading mechanism that enhances specificity and prevents an antiviral response upon encounter with host RNA molecules.

scholarly journals CryoEM structures of MDA5-dsRNA filaments at different stages of ATP hydrolysis

2018 ◽  
Author(s):  
Qin Yu ◽  
Kun Qu ◽  
Yorgo Modis
Keyword(s):  
Rna Binding ◽  
Atp Hydrolysis ◽  
Type I ◽  
List Type ◽  
Base Pairs ◽  
Nucleotide Analogs ◽  
Double Stranded Rna ◽  
Transition State Analogs ◽  
Helical Twist ◽  
Dsrna Binding

SummaryDouble-stranded RNA (dsRNA) is a potent proinflammatory signature of viral infection. Long cytosolic dsRNA is recognized by MDA5. The cooperative assembly of MDA5 into helical filaments on dsRNA nucleates the assembly of a multiprotein type-I-interferon signaling platform. Here, we determined cryoEM structures of MDA5-dsRNA filaments with different helical twists and bound nucleotide analogs, at resolutions sufficient to build and refine atomic models. The structures identify the filament forming interfaces, which encode the dsRNA binding cooperativity and length specificity of MDA5. The predominantly hydrophobic interface contacts confer flexibility, reflected in the variable helical twist within filaments. Mutation of filament-forming residues can result in loss or gain of signaling activity. Each MDA5 molecule spans 14 or 15 RNA base pairs, depending on the twist. Variations in twist also correlate with variations in the occupancy and type of nucleotide in the active site, providing insights on how ATP hydrolysis contributes to MDA5-dsRNA recognition.eTOCStructures of MDA5 bound to double-stranded RNA reveal a flexible, predominantly hydrophobic filament forming interface. The filaments have variable helical twist. Structures determined with ATP and transition state analogs show how the ATPase cycle is coupled to changes in helical twist, the mode of RNA binding and the length of the RNA footprint of MDA5.HighlightsCryoEM structures of MDA5-dsRNA filaments determined for three catalytic statesFilament forming interfaces are flexible and predominantly hydrophobicMutation of filament-forming residues can cause loss or gain of IFN-β signalingATPase cycle is coupled to changes in filament twist and size of the RNA footprint

CP Poly(A) RNA Binding Immunity via Outside-in Glycosyltransfer with MT of BTRC-Activating L12535 and PIN1 Subnetworks for Cognition in PFC|CD14

2020 ◽  
Author(s):  
Lin Wang ◽  
Qingchun Chen ◽  
Haitao Feng ◽  
Minghu Jiang ◽  
Juxiang Huang ◽  
...  
Keyword(s):  
Immune Response ◽  
Network Inference ◽  
Rna Binding ◽  
Biological Process ◽  
Cellular Component ◽  
Innate Immune ◽  
Molecular Function ◽  
Ubiquitin Protein Ligase ◽  
The Common ◽  
Cluster Of Differentiation

Abstract Background: Ras suppressor protein 1 (L12535) and peptidylprolyl cis/trans isomerase NIMA-interacting 1 (PIN1) common molecular and knowledge subnetworks containing microtubule associated protein 1B-MAP1B_1 (upstream) related to cognition by references were identified in human left hemisphere, based on our established significant high expression beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC)-activating downstream Gene (protein) reconstruction network inference (GRNInfer) and Database for Annotation, Visualization and Integrated Discovery (DAVID).Results: Our results show the common molecules exostosin-like glycosyltransferase 2 (EXTL2) interaction with MAP1B_1 both activating TERF1_1 with HSP90AB1 from BTRC-activating downstream GRNInfer database; The common biological process and molecular function of MAP1B_1, TERF1_1 as microtubule (MT) binding; HSP90AB1 as poly(A) RNA binding; BTRC, HSP90AB1, PIN1 as innate immune response from BTRC-activating downstream DAVID database; The common cellular component of EXTL2 at integral component of membrane; MAP1B_1, HSP90AB1, TERF1_1 at cytoplasm (CP); The common tissue distributions of L12535 and PIN1 in Prefrontal Cortex (PFC), PB cluster of differentiation (CD)14+Monocytes.Conclusions: We propose and mutual positively verify CP poly(A) RNA binding immunity via outside-in glycosyltransfer with MT of BTRC-activating L12535 and PIN1 subnetworks for cognition in PFC|CD14.

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