Functional Dissection of an Innate Immune Response by a Genome-Wide RNAi Screen
Open accessAbstract
The innate immune system is ancient and highly conserved. It is the first line of defense and the only recognizable immune system in the vast majority of metazoans. Signaling events that convert pathogen detection into a defense response are central to innate immunity. Drosophila has emerged as an invaluable model organism for studying this regulation. Activation of the NF-kappaB family member Relish by the caspase-8 homolog Dredd is a central, but still poorly understood, signaling module in the response to gram-negative bacteria. To identify the genes contributing to this regulation, we produced double-stranded RNAs corresponding to the conserved genes in the Drosophila genome and used this resource in genome-wide RNA interference screens. We identified numerous inhibitors and activators of immune reporters in a cell culture model. Epistatic interactions and phenotypes defined a hierarchy of gene action and demonstrated that the conserved gene sickie is required for activation of Relish. We also showed that a second gene, defense repressor 1, encodes a product with characteristics of an inhibitor of apoptosis protein that inhibits the Dredd caspase to maintain quiescence of the signaling pathway. Molecular analysis revealed that Defense repressor 1 is upregulated by Dredd in a feedback loop. We propose that interruption of this feedback loop contributes to signal transduction.
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The D. melanogaster Dnr1 gene is a distant homolog of mammalian IDOL.
“The D. melanogaster Dnr1 gene is a distant homolog of mammalian IDOL (28).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [28]
The Results section (Figure 4A; page unavailable) compares Dnr1’s amino acid sequence with human MIR, and the accompanying text calls Dnr1 a conserved protein. Our copy does not identify human MIR as IDOL or describe the relationship to IDOL specifically, so it supports a human sequence similarity but not the named homolog in the claim. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDnr1 is an inhibitor of the inflammatory IMD pathway in flies.
“Dnr1 is an inhibitor of the inflammatory IMD pathway in flies (28).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [28]
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- Authors
- Foley, E., & O'Farrell, P. H.
- Affiliations
- University of California, San Francisco (US)
- ORCID
- Foley, Edan
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2004-06-22
- Volume
- 2
- Issue
- 8
- Pages
- e203
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC434151
- OpenAlex
- W1994557554
- Cited by
- 238
- References
- 55
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 11 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 11 · 2017: 5 · 2016: 5 · 2015: 10 · 2014: 13 · 2013: 11 · 2012: 9
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- University of California, San Francisco
- National Institute of General Medical Sciences (GM 60988, R01GM060988)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Invertebrate Immune Response Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- innate immunity, Drosophila, Relish, caspase-8, NF-κB signaling, Gram-negative bacteria, inhibitor of apoptosis proteins, feedback loops, epistasis, immune gene regulation, RNAi screen
- MeSH terms
- Amino Acid Sequence, Animals, beta-Galactosidase, Cell Line, Drosophila, Epistasis, Genetic, Gene Expression Regulation, Image Processing, Computer-Assisted, Immunity, Innate, Microscopy, Fluorescence, Models, Biological, Models, Genetic, Molecular Sequence Data, Phenotype, RNA, Double-Stranded, Transcription Factors, Blotting, Western, Signal Transduction, Gene Library, Up-Regulation, NF-kappa B, Genome, Sequence Homology, Amino Acid, Genes, Reporter, Insect Proteins, Caspases, Drosophila Proteins, RNA Interference, Caspase 8
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