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Genome-wide RNA interference in Drosophila cells identifies G protein-coupled receptor kinase 2 as a conserved regulator of NF-kappaB signaling.
(Webster)ORCID iD: 0000-0003-0772-3431
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2010 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 11Article in journal (Refereed) Published
Abstract [en]

Because NF-kappaB signaling pathways are highly conserved in evolution, the fruit fly Drosophila melanogaster provides a good model to study these cascades. We carried out an RNA interference (RNAi)-based genome-wide in vitro reporter assay screen in Drosophila for components of NF-kappaB pathways. We analyzed 16,025 dsRNA-treatments and identified 10 novel NF-kappaB regulators. Of these, nine dsRNA-treatments affect primarily the Toll pathway. G protein-coupled receptor kinase (Gprk)2, CG15737/Toll pathway activation mediating protein, and u-shaped were required for normal Drosomycin response in vivo. Interaction studies revealed that Gprk2 interacts with the Drosophila IkappaB homolog Cactus, but is not required in Cactus degradation, indicating a novel mechanism for NF-kappaB regulation. Morpholino silencing of the zebrafish ortholog of Gprk2 in fish embryos caused impaired cytokine expression after Escherichia coli infection, indicating a conserved role in NF-kappaB signaling. Moreover, small interfering RNA silencing of the human ortholog GRK5 in HeLa cells impaired NF-kappaB reporter activity. Gprk2 RNAi flies are susceptible to infection with Enterococcus faecalis and Gprk2 RNAi rescues Toll(10b)-induced blood cell activation in Drosophila larvae in vivo. We conclude that Gprk2/GRK5 has an evolutionarily conserved role in regulating NF-kappaB signaling.

Place, publisher, year, edition, pages
2010. Vol. 184, no 11
National Category
Immunology Genetics
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URN: urn:nbn:se:uu:diva-286594DOI: 10.4049/jimmunol.1000261PubMedID: 20421637OAI: oai:DiVA.org:uu-286594DiVA: diva2:921781
Available from: 2016-04-21 Created: 2016-04-21 Last updated: 2017-11-30

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Schmid, Martin Rudolf

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