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Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation

Insects depend on the innate immune response for defense against a wide array of pathogens. Central to Drosophila immunity are antimicrobial peptides (AMPs), released into circulation when pathogens trigger either of the two widely studied signal pathways, Toll or IMD. The Toll pathway responds to i...

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Autores principales: Tang, Ruijuan, Huang, Wuren, Guan, Jingmin, Liu, Qiuning, Beerntsen, Brenda T., Ling, Erjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376203/
https://www.ncbi.nlm.nih.gov/pubmed/34370736
http://dx.doi.org/10.1371/journal.pgen.1009718
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author Tang, Ruijuan
Huang, Wuren
Guan, Jingmin
Liu, Qiuning
Beerntsen, Brenda T.
Ling, Erjun
author_facet Tang, Ruijuan
Huang, Wuren
Guan, Jingmin
Liu, Qiuning
Beerntsen, Brenda T.
Ling, Erjun
author_sort Tang, Ruijuan
collection PubMed
description Insects depend on the innate immune response for defense against a wide array of pathogens. Central to Drosophila immunity are antimicrobial peptides (AMPs), released into circulation when pathogens trigger either of the two widely studied signal pathways, Toll or IMD. The Toll pathway responds to infection by Gram-positive bacteria and fungi while the IMD pathway is activated by Gram-negative bacteria. During activation of the IMD pathway, the NF-κB-like transcription factor Relish is phosphorylated and then cleaved, which is crucial for IMD-dependent AMP gene induction. Here we show that loss-of-function mutants of the unconventional histone variant H2Av upregulate IMD-dependent AMP gene induction in germ-free Drosophila larvae and adults. After careful dissection of the IMD pathway, we found that Relish has an epistatic relationship with H2Av. In the H2Av mutant larvae, SUMOylation is down-regulated, suggesting a possible role of SUMOylation in the immune phenotype. Eventually we demonstrated that Relish is mostly SUMOylated on amino acid K823. Loss of the potential SUMOylation site leads to significant auto-activation of Relish in vivo. Further work indicated that H2Av regulates Relish SUMOylation after physically interacting with Su(var)2-10, the E3 component of the SUMOylation pathway. Biochemical analysis suggested that SUMOylation of Relish prevents its cleavage and activation. Our findings suggest a new mechanism by which H2Av can negatively regulate, and thus prevent spontaneous activation of IMD-dependent AMP production, through facilitating SUMOylation of the NF-κB like transcription factor Relish.
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spelling pubmed-83762032021-08-20 Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation Tang, Ruijuan Huang, Wuren Guan, Jingmin Liu, Qiuning Beerntsen, Brenda T. Ling, Erjun PLoS Genet Research Article Insects depend on the innate immune response for defense against a wide array of pathogens. Central to Drosophila immunity are antimicrobial peptides (AMPs), released into circulation when pathogens trigger either of the two widely studied signal pathways, Toll or IMD. The Toll pathway responds to infection by Gram-positive bacteria and fungi while the IMD pathway is activated by Gram-negative bacteria. During activation of the IMD pathway, the NF-κB-like transcription factor Relish is phosphorylated and then cleaved, which is crucial for IMD-dependent AMP gene induction. Here we show that loss-of-function mutants of the unconventional histone variant H2Av upregulate IMD-dependent AMP gene induction in germ-free Drosophila larvae and adults. After careful dissection of the IMD pathway, we found that Relish has an epistatic relationship with H2Av. In the H2Av mutant larvae, SUMOylation is down-regulated, suggesting a possible role of SUMOylation in the immune phenotype. Eventually we demonstrated that Relish is mostly SUMOylated on amino acid K823. Loss of the potential SUMOylation site leads to significant auto-activation of Relish in vivo. Further work indicated that H2Av regulates Relish SUMOylation after physically interacting with Su(var)2-10, the E3 component of the SUMOylation pathway. Biochemical analysis suggested that SUMOylation of Relish prevents its cleavage and activation. Our findings suggest a new mechanism by which H2Av can negatively regulate, and thus prevent spontaneous activation of IMD-dependent AMP production, through facilitating SUMOylation of the NF-κB like transcription factor Relish. Public Library of Science 2021-08-09 /pmc/articles/PMC8376203/ /pubmed/34370736 http://dx.doi.org/10.1371/journal.pgen.1009718 Text en © 2021 Tang et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tang, Ruijuan
Huang, Wuren
Guan, Jingmin
Liu, Qiuning
Beerntsen, Brenda T.
Ling, Erjun
Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation
title Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation
title_full Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation
title_fullStr Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation
title_full_unstemmed Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation
title_short Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation
title_sort drosophila h2av negatively regulates the activity of the imd pathway via facilitating relish sumoylation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376203/
https://www.ncbi.nlm.nih.gov/pubmed/34370736
http://dx.doi.org/10.1371/journal.pgen.1009718
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