Mitochondria-localized ZNFX1 functions as a dsRNA sensor to initiate antiviral responses via MAVS
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ABSTRACT:
PROVIDER: PRJNA549611 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9317860_1.fastq.gz | Fastqsanger.gz | |||
| SRR9317860_2.fastq.gz | Fastqsanger.gz | |||
| SRR9317855_1.fastq.gz | Fastqsanger.gz | |||
| SRR9317855_2.fastq.gz | Fastqsanger.gz | |||
| SRR9317856_1.fastq.gz | Fastqsanger.gz |
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Project description:Pattern recognition receptors (PRRs)-mediated innate immune responses are critical for host defense against microbial pathogens including RNA/DNA viruses. A growing number of coding genes and genes originally defined as non-coding RNAs (ncRNAs) are found to encode short peptides or proteins, named microproteins. However, the landscape of microproteins in responsive to virus infection and the functions of these microproteins remain uncharacterized. Here, we systematically identified microproteins, both from coding and non-coding genes, that are responsive to Vesicular Stomatitis Virus (VSV) infection. Among which, a highly conserved, endoplasmic reticulum (ER) membrane-localized microprotein, , MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrial localized MAVS protein, inhibiting the aggregation of MAVS and the activation of downstream type I interferon (IFN) signaling pathway. The critical role of MAVI1 was highlighted that viral infection was significantly attenuated and survival rate was significantly increased in Mavi1 knockout mice in vivo. A peptide inhibitor targeting the interaction between MAVI1 and MAVS is potent in activating the type I IFN signaling and defending viral infection both in vitro and in vivo. Our findings uncovered that microproteins could play critical roles in regulating antiviral innate immune responses via cross-organelle interaction, and targeting microproteins might represent a potential therapeutic avenue for treating viral infection in clinic.
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Project description:Eukaryotic cells recognize intracellular pathogens through pattern recognition receptors, including sensors of aberrant nucleic acid structures. Sensors of double-stranded RNA (dsRNA) are known to detect replication intermediates of RNA viruses. It has been suggested that annealing of mRNA from symmetrical transcription of both top and bottom strands of DNA virus genomes can produce dsRNA during infection. Supporting this hypothesis, nearly all DNA viruses encode inhibitors of dsRNA-recognition pathways. However, direct evidence that DNA viruses produce dsRNA is lacking. Contrary to dogma, we show that the nuclear-replicating DNA virus adenovirus (AdV) does not produce detectable levels of dsRNA during infection. In contrast, abundant dsRNA is detected within the nucleus of cells infected with AdV mutants that lack the virus-directed ubiquitin ligase required for efficient processing of viral RNA. In the presence of nuclear dsRNA, the cytoplasmic dsRNA sensor PKR is relocalized and activated within the nucleus. Accumulation of viral dsRNA occurs in the late phase of infection, when unspliced viral transcripts form intron/exon base pairs between top and bottom strand transcripts. We propose that DNA viruses actively promote efficient splicing and mRNA processing to limit dsRNA formation, thus avoiding detection and restriction by host nucleic acid sensors.
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Project description:MAVS-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remains uncertain. Here, we demonstrate that host MAVS pathway drives accelerated tumor growth and impairs antitumor immunity, while MAVS knockout in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, the CD8+ T cell priming capacity is enhanced by lack of functional MAVS in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of RIG-I/MAVS cascade activates non-canonical NF-κB pathway and in turn induces IL-12 production by DCs, resulting in CD8+ T cell: DC crosstalk licensed by IFN-γ and IL-12. Moreover, ablation of host MAVS sensitizes tumors to immunotherapy and attenuates radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings identify that host MAVS pathway acts as an immune checkpoint of DC-driven antitumor immunity, indicating the development of DC-based immunotherapies through MAVS signaling antagonism.
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Project description:DExD/H-box helicases play essential roles in RNA metabolism, and emerging data suggests that they have additional functions in antiviral immunity across species. However, little is known about this evolutionarily conserved family in antiviral responses in lower species. Here, through isolation of poly(I:C)-binding proteins in amphioxus, an extant basal chordate, we found that DExD/H-box helicases DHX9, DHX15, and DDX23 are responsible for cytoplasmic dsRNA detection in amphioxus. Since the antiviral roles of DDX23 have not been characterized in mammals, we performed further poly(I:C) pull-down assays and found that human DDX23 binds to LMW poly(I:C) through its N-terminal region, suggesting that DDX23 is an evolutionarily conserved dsRNA sensor. Knockdown of human DDX23 enhanced the replication of VSV and reduced the activation of the NF-?B and IRF3. Moreover, when stimulated with poly(I:C) or VSV, human DDX23 translocated from the nucleus to the cytoplasm and formed complexes with TRIF or MAVS to initiate downstream signaling. Collectively, this comparative immunological study not only defined DDX23 as an emerging nuclear pattern recognition receptor (PRR) for the innate sensing of an RNA virus, but also extended the essential role of the DExD/H helicase family in viral RNA sensing from mammals to basal chordates.
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