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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Veröffentlicht in:PLoS genetics 2021-08, Vol.17 (8), p.e1009718-e1009718
Hauptverfasser: Tang, Ruijuan, Huang, Wuren, Guan, Jingmin, Liu, Qiuning, Beerntsen, Brenda T, Ling, Erjun
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creator Tang, Ruijuan
Huang, Wuren
Guan, Jingmin
Liu, Qiuning
Beerntsen, Brenda T
Ling, Erjun
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.
doi_str_mv 10.1371/journal.pgen.1009718
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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. 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subjects Amino acids
Animals
Antimicrobial Cationic Peptides - genetics
Antimicrobial peptides
Bacteria
Biochemical analysis
Biology and life sciences
Cellular signal transduction
Drosophila
Drosophila melanogaster - genetics
Drosophila melanogaster - metabolism
Drosophila Proteins - genetics
Drosophila Proteins - immunology
Drosophila Proteins - metabolism
Drosophila Proteins - physiology
Enzymes
Epistasis
Gene expression
Gene Expression - genetics
Gene Expression Regulation - genetics
Genetic aspects
Genetic regulation
Germfree
Gram-negative bacteria
Gram-positive bacteria
Histones
Histones - metabolism
Histones - physiology
Immune response
Immunity, Innate - genetics
Innate immunity
Insects
Kinases
Localization
Mammals
Medicine and Health Sciences
Microbiota
Mutants
NF-kappa B - genetics
NF-κB protein
Pathogens
Peptides
Phenotypes
Physiological aspects
Proteins
Research and Analysis Methods
Signal Transduction - genetics
SUMO protein
Sumoylation - genetics
Toll-Like Receptors
Transcription factors
Transcription Factors - genetics
Transcription Factors - metabolism
title Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation
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