Targeting a key disulfide linkage to regulate RIG-I condensation and cytosolic RNA-sensing
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1194045 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31602678_1.fastq.gz | Fastqsanger.gz | |||
| SRR31602678_2.fastq.gz | Fastqsanger.gz | |||
| SRR31602679_1.fastq.gz | Fastqsanger.gz | |||
| SRR31602679_2.fastq.gz | Fastqsanger.gz | |||
| SRR31602680_1.fastq.gz | Fastqsanger.gz |
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Project description:Maintaining innate immune homeostasis is critical for preventing infections and autoimmune diseases, but the effective interventions are lacking. Here, we identified Cys864-Cys869-mediated intermolecular disulfide-linkage formation as a critical step for human RIG-I activation that can be bidirectionally regulated to control innate immune homeostasis. The viral-stimulated Cys864-Cys869 disulfide-linkage mediates conjugation of an SDS-resistant RIG-I oligomer, which prevents RIG-I degradation by E3 ubiquitin-ligase MIB2 and is necessary for RIG-I to perform liquid-liquid phase separation to compartmentalize downstream signalsome, thereby stimulating IFN-I signaling. The corresponding C865S ‘knock-in’ caused defect of oligomerization and LLPS in mouse RIG-I, which inhibited innate immunity, resulting in increased viral load and mortality in mice. Through generating covalent Cys864-Cys869 linkage by unnatural amino-acid and developing interfering peptide to block Cys864-Cys869 residues, we bidirectionally regulate RIG-I activities in human diseases. These findings provide novel and in-depth insights on mechanism of RIG-I activation, develop methodologies that hold promising implications in clinics
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Project description:The RIG-I like receptors (RLRs) RIG-I and MDA5 are cytosolic RNA helicases best characterized as restriction factors for RNA viruses. However, evidence suggests RLRs participate in innate immune recognition of other pathogens, including DNA viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi's sarcoma and primary effusion lymphoma (PEL). We demonstrate that RIG-I and MDA5 restrict KSHV lytic reactivation in PEL. By performing fRIP-Seq, we define the in vivo RLR substrates and demonstrate that RIG-I and MDA5-mediated restriction is facilitated exclusively by the recognition of host-derived RNAs.
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Project description:The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5M-bM-^@M-^Y triphosphate (5M-bM-^@M-^Yppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5M-bM-^@M-^YpppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, andinduction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN)signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5M-bM-^@M-^YpppRNA, and not by IFNM-NM-1-2bthat included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5M-bM-^@M-^YpppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5M-bM-^@M-^YpppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach providestranscriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5M-bM-^@M-^YpppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents. Kinetic analysis of A549 cells treated with 5'pppRNA and analyzed at 1h, 2h, 4h, 6h, 8h, 12h, 24h or 48h.
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