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Polydnavirus Ank proteins bind NF-?B homodimers and inhibit processing of Relish.

ABSTRACT: Recent studies have greatly increased understanding of how the immune system of insects responds to infection, whereas much less is known about how pathogens subvert immune defenses. Key regulators of the insect immune system are Rel proteins that form Nuclear Factor-?B (NF-?B) transcription factors, and inhibitor ?B (I?B) proteins that complex with and regulate NF-?Bs. Major mortality agents of insects are parasitoid wasps that carry immunosuppressive polydnaviruses (PDVs). Most PDVs encode ank genes that share features with I?Bs, while our own prior studies suggested that two ank family members from Microplitis demolitor bracovirus (MdBV) (Ank-H4 and Ank-N5) behave as I?B mimics. However, the binding affinities of these viral mimics for Rel proteins relative to endogenous I?Bs remained unclear. Surface plasmon resonance (SPR) and co-immunoprecipitation assays showed that the I?B Cactus from Drosophila bound Dif and Dorsal homodimers more strongly than Relish homodimers. Ank-H4 and -N5 bound Dif, Dorsal and Relish homodimers with higher affinity than the I?B domain of Relish (Rel-49), and also bound Relish homodimers more strongly than Cactus. Ank-H4 and -N5 inhibited processing of compound Relish and reduced the expression of several antimicrobial peptide genes regulated by the Imd signaling pathway in Drosophila mbn2 cells. Studies conducted in the natural host Pseudoplusia includens suggested that parasitism by M. demolitor also activates NF-?B signaling and that MdBV inhibits this response. Overall, our data provide the first quantitative measures of insect and viral I?B binding affinities, while also showing that viral mimics disable Relish processing.

SUBMITTER: Bitra K

PROVIDER: S-EPMC3359993 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Polydnavirus Ank proteins bind NF-κB homodimers and inhibit processing of Relish.

Bitra Kavita K Suderman Richard J RJ Strand Michael R MR

PLoS pathogens 20120524 5

Recent studies have greatly increased understanding of how the immune system of insects responds to infection, whereas much less is known about how pathogens subvert immune defenses. Key regulators of the insect immune system are Rel proteins that form Nuclear Factor-κB (NF-κB) transcription factors, and inhibitor κB (IκB) proteins that complex with and regulate NF-κBs. Major mortality agents of insects are parasitoid wasps that carry immunosuppressive polydnaviruses (PDVs). Most PDVs encode ank ...[more]

PMID: 22654665

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Project description:Orientia tsutsugamushi causes scrub typhus, a potentially fatal infection that threatens over one billion people. Nuclear translocation of the transcription factor, NF-?B, is the central initiating cellular event in the antimicrobial response. Here, we report that NF-?B p65 nuclear accumulation and NF-?B-dependent transcription are inhibited in O. tsutsugamushi infected HeLa cells and/or primary macrophages, even in the presence of TNF?. The bacterium modulates p65 subcellular localization by neither degrading it nor inhibiting I?B? degradation. Rather, it exploits host exportin 1 to mediate p65 nuclear export, as this phenomenon is leptomycin B-sensitive. O. tsutsugamushi antagonizes NF-?B-activated transcription even when exportin 1 is inhibited and NF-?B consequently remains in the nucleus. Two ankyrin repeat-containing effectors (Anks), Ank1 and Ank6, each of which possess a C-terminal F-box and exhibit 58.5% amino acid identity, are linked to the pathogen's ability to modulate NF-?B. When ectopically expressed, both translocate to the nucleus, abrogate NF-?B-activated transcription in an exportin 1-independent manner, and pronouncedly reduce TNF?-induced p65 nuclear levels by exportin 1-dependent means. Flag-tagged Ank 1 and Ank6 co-immunoprecipitate p65 and exportin 1. Both also bind importin ?1, a host protein that is essential for the classical nuclear import pathway. Importazole, which blocks importin ?1 activity, abrogates Ank1 and Ank6 nuclear translocation. The Ank1 and Ank6 regions that bind importin ?1 also mediate their transport into the nucleus. Yet, these regions are distinct from those that bind p65/exportin 1. The Ank1 and Ank6 F-box and the region that lies between it and the ankyrin repeat domain are essential for blocking p65 nuclear accumulation. These data reveal a novel mechanism by which O. tsutsugamushi modulates the activity and nuclear transport of NF-?B p65 and identify the first microbial proteins that co-opt both importin ?1 and exportin 1 to antagonize a critical arm of the antimicrobial response.

Dataset Information

Polydnavirus Ank proteins bind NF-?B homodimers and inhibit processing of Relish.

Publications

Polydnavirus Ank proteins bind NF-κB homodimers and inhibit processing of Relish.

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