Adenosine deaminase and deoxyadenosine regulate intracellular immune response in C. elegans

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 111950 - 111950

Published: Feb. 4, 2025

Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are enzymes in the salvage pathway, which recycles purines to meet cellular demands. Mutations of these humans cause inflammatory immunodeficiency syndromes, but mechanisms not well understood. Prior work nematode Caenorhabditis elegans demonstrated that loss PNP ortholog PNP-1 induced an immune response called intracellular pathogen (IPR). Here, we show enzyme upstream ADAH-1 (ADA homolog) also induces IPR promotes resistance against pathogens. Unlike PNP-1, is essential for organismal development. Importantly, find supplementation deoxyadenosine, a substrate ADA, pathogens C. elegans, finding extend human cells. Thus, mutations ADA induce innate immunity through increased phenomenon conserved from humans.

Language: Английский

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Similarities in the induction of the intracellular pathogen response in Caenorhabditis elegans and the type I interferon response in mammals

BioEssays, Journal Year: 2023, Volume and Issue: 45(11)

Published: Sept. 4, 2023

Although the type-I interferon (IFN-I) response is considered vertebrate-specific, recent findings about Intracellular Pathogen Response (IPR) in nematode Caenorhabditis elegans indicate that there are similarities between these two transcriptional immunological programs. The IPR induced during infection with natural intracellular fungal and viral pathogens of intestine promotes resistance against pathogens. Similarly, IFN-I by viruses other infection. Whether evolved a divergent or convergent manner an unanswered exciting question, which could be addressed further studies immunity C. simple host organisms. Here we highlight similar roles played RIG-I-like receptors, purine metabolism enzymes, proteotoxic stressors, transcription factors to induce response, as well consequences defense programs on organismal development.

Language: Английский

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Investigating the Evolution of Drosophila STING-Dependent Antiviral Innate Immunity by Multispecies Comparison of 2′3′-cGAMP Responses

Molecular Biology and Evolution, Journal Year: 2024, Volume and Issue: 41(3)

Published: Feb. 20, 2024

Viruses represent a major threat to all animals, which defend themselves through induction of large set virus-stimulated genes that collectively control the infection. In vertebrates, these include interferons play critical role in amplification response Virus- and interferon-stimulated restriction factors targeting different steps viral replication cycle, addition molecules associated with inflammation adaptive immunity. Predictably, antiviral evolve dynamically pressure. As result, each animal has unique arsenal genes. Here, we exploit capacity experimentally activate evolutionarily conserved stimulator IFN (STING) signaling pathway by injection cyclic dinucleotide 2'3'-cyclic guanosine monophosphate-adenosine monophosphate into flies define repertoire STING-regulated 10 Drosophila species, spanning 40 million years evolution. Our data reveal factors, including STING itself, cGAS-like-receptor, factor pastel, protein Vago, but also 2 key components RNA interference pathway, Dicer-2, Argonaute2. addition, identify unknown species- or lineage-specific have not been previously resistance viruses. provide insight core pave way for characterization effectors.

Language: Английский

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Caenorhabditis elegans RIG-I-like receptor DRH-1 signals via CARDs to activate antiviral immunity in intestinal cells

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(29)

Published: July 9, 2024

Upon sensing viral RNA, mammalian RIG-I-like receptors (RLRs) activate downstream signals using caspase activation and recruitment domains (CARDs), which ultimately promote transcriptional immune responses that have been well studied. In contrast, the signaling mechanisms for invertebrate RLRs are much less clear. For example, Caenorhabditis elegans RLR DRH-1 lacks annotated CARDs up-regulates distinct output of RNA interference. Here, we found similar to mammal RLRs, through two tandem (2CARD) induce a response. Expression DRH-1(2CARD) alone in intestine was sufficient gene expression, increase resistance, thermotolerance, phenotype previously associated with C. . We also is required demonstrate subcellular colocalization puncta double-stranded inside cytoplasm intestinal cells upon infection. Altogether, our results reveal mechanistic spatial insights into antiviral , highlighting unexpected parallels between mammals.

Language: Английский

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Proteasome inhibition triggers tissue-specific immune responses against different pathogens in C. elegans

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(3), P. e3002543 - e3002543

Published: March 11, 2024

Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF up-regulates proteostasis capacity after blockade of proteasome and also promotes bacterial infection nematode Caenorhabditis elegans . has 3 isoforms, SKN-1A/NRF1 isoform, particular, regulates proteasomal gene expression upon dysfunction as part a bounce-back response. We report here that, contrast to previously reported role SKN-1 promoting infection, loss-of-function mutants skn-1a its activating enzymes ddi-1 png-1 show constitutive immune response programs natural eukaryotic pathogens C These are oomycete recognition (ORR), which oomycetes that infect through epidermis, intracellular (IPR), intestine-infecting microsporidia. Consequently, increased both microsporidia infections. almost all ORR/IPR genes induced common between these regulated by interestingly, specific can be distinct tissues depending on exact trigger. Furthermore, we increasing function significantly reduces oomycete-mediated induction multiple ORR markers. Altogether, our findings demonstrate regulation keeps innate responses check tissue-specific manner epidermis intestine.

Language: Английский

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Caenorhabditis elegans immune responses to microsporidia and viruses

Developmental & Comparative Immunology, Journal Year: 2024, Volume and Issue: 154, P. 105148 - 105148

Published: Feb. 5, 2024

The model organism Caenorhabditis elegans is susceptible to infection by obligate intracellular pathogens, specifically microsporidia and viruses. These pathogens infect intestinal cells, or, for some microsporidia, epidermal cells. Strikingly, cell infections viruses or trigger a common transcriptional response, activated in part the ZIP-1 transcription factor. Among strongest genes this response are ubiquitin-pathway members of pals family, an intriguing gene family with cross-regulations different genomic clusters. Some induced participate host defense against example through ubiquitin-mediated inhibition. Other mechanisms defend viral infections, including antiviral RNA interference uridylation. various immune responses altered environmental factors intraspecific genetic variation host. were first isolated 15 years ago much remains be discovered using C. genetics; also, other may yet discovered.

Language: Английский

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The importance of IP6 for ADAR RNA-editing enzymes and antiviral defense

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(4)

Published: Jan. 21, 2025

Language: Английский

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Simple Worm, Complex Disorder: Studying Down Syndrome Mechanisms in the Unassuming Model C. elegans

Published: Jan. 1, 2025

Language: Английский

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Cap-adjacent 2’-O-ribose methylation of RNA inC. elegansis required for postembryonic growth and germline development in the presence of the decapping exonuclease EOL-1

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

ABSTRACT Cap-adjacent 2’- O -ribose methylation (cOMe) of the first two transcribed nucleotides is a conserved feature RNA polymerase II transcripts in many eukaryotes. In mammals, these modifications are key to transcript surveillance system that regulates interferon response, but broader functions cOMe remain poorly understood. To understand role C. elegans , we functionally characterised methyltransferases (CMTR-1 and CMTR-2) responsible for installing modifications. These enzymes have distinct expression patterns, protein interaction partners loss function phenotypes. Loss CMTR-1 causes dramatic reductions cOMe, impaired growth sterility. contrast, animals lacking CMTR-2 superficially wild-type phenotype, though enhances severity cmtr-1 mutant phenotype. Depletion downregulation associated with germline sex determination upregulation those involved intracellular pathogen response (IPR). We show absence decapping exonuclease, EOL-1, an IPR component, completely suppresses sterility defects caused CMTR-1, suggesting EOL-1 degrades cellular cOMe. Our work shows physiological relevance protecting from exonucleases, raising possibility plays RNA-mediated immune beyond vertebrates.

Language: Английский

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Conserved chromatin regulators control the transcriptional immune response to intracellular pathogens in Caenorhabditis elegans

PLoS Genetics, Journal Year: 2025, Volume and Issue: 21(4), P. e1011444 - e1011444

Published: April 7, 2025

Robust transcriptional responses are critical for defense against infection. However, unrestrained immune can cause negative impacts such as damaging inflammation and slowed development. Here, we find that a class of regulators previously associated with regulation development in Caenorhabditis elegans , is also involved repressing responses. Specifically, through forward genetics, loss lin-15B leads to constitutive expression Intracellular Pathogen Response (IPR) genes. encodes repressor conserved THAP domain the DRM chromatin remodeling complex regulates C. We show mutants have increased resistance natural intracellular pathogens, induction IPR genes relies on MES-4 histone methyltransferase. extend our analyses other NuRD factors, well SUMOylation modifiers, showing broad range chromatin-related factors repress gene expression. Altogether these findings suggest may facilitate part by pathogens.

Language: Английский

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