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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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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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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1009718</identifier><identifier>PMID: 34370736</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>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</subject><ispartof>PLoS genetics, 2021-08, Vol.17 (8), p.e1009718-e1009718</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Tang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Tang et al 2021 Tang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c726t-a7983504e2fb141b79e19110451a3b5885025577b7b057834f6df59ea2c6e3a73</citedby><cites>FETCH-LOGICAL-c726t-a7983504e2fb141b79e19110451a3b5885025577b7b057834f6df59ea2c6e3a73</cites><orcidid>0000-0002-2101-2372 ; 0000-0001-7193-3201</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376203/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376203/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34370736$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Eleftherianos, Ioannis</contributor><creatorcontrib>Tang, Ruijuan</creatorcontrib><creatorcontrib>Huang, Wuren</creatorcontrib><creatorcontrib>Guan, Jingmin</creatorcontrib><creatorcontrib>Liu, Qiuning</creatorcontrib><creatorcontrib>Beerntsen, Brenda T</creatorcontrib><creatorcontrib>Ling, Erjun</creatorcontrib><title>Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><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.</description><subject>Amino acids</subject><subject>Animals</subject><subject>Antimicrobial Cationic Peptides - genetics</subject><subject>Antimicrobial peptides</subject><subject>Bacteria</subject><subject>Biochemical analysis</subject><subject>Biology and life sciences</subject><subject>Cellular signal transduction</subject><subject>Drosophila</subject><subject>Drosophila melanogaster - genetics</subject><subject>Drosophila melanogaster - metabolism</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - immunology</subject><subject>Drosophila Proteins - metabolism</subject><subject>Drosophila Proteins - physiology</subject><subject>Enzymes</subject><subject>Epistasis</subject><subject>Gene expression</subject><subject>Gene Expression - genetics</subject><subject>Gene Expression Regulation - genetics</subject><subject>Genetic aspects</subject><subject>Genetic regulation</subject><subject>Germfree</subject><subject>Gram-negative bacteria</subject><subject>Gram-positive bacteria</subject><subject>Histones</subject><subject>Histones - metabolism</subject><subject>Histones - physiology</subject><subject>Immune response</subject><subject>Immunity, Innate - genetics</subject><subject>Innate immunity</subject><subject>Insects</subject><subject>Kinases</subject><subject>Localization</subject><subject>Mammals</subject><subject>Medicine and Health Sciences</subject><subject>Microbiota</subject><subject>Mutants</subject><subject>NF-kappa B - genetics</subject><subject>NF-κB protein</subject><subject>Pathogens</subject><subject>Peptides</subject><subject>Phenotypes</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Signal Transduction - genetics</subject><subject>SUMO protein</subject><subject>Sumoylation - genetics</subject><subject>Toll-Like Receptors</subject><subject>Transcription factors</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqVk1Fv0zAQxyMEYmPwDRBEQkLw0GLHcZy8IFUbsEoblTbGq3VJLokrN-5ip9Bvj7N2U4P2APJD7PPv_7-c7QuC15RMKRP009L0XQt6uq6xnVJCMkHTJ8Ex5ZxNREzipwfzo-CFtUtCGE8z8Tw4YjETRLDkOGjOOmPNulEawvNotglbrMGpDept2GHda3BoQ9dgCIUPK7cNTXW3nl-ehWtwzS_YhhsFYQWF0sp5cVuHV6iVbcLrm8vF1lso074MnlWgLb7af0-Cm69ffpyeTy4W3-ans4tJIaLETUBkKeMkxqjKaUxzkSHNKCUxp8BynqacRJwLkYuccJGyuErKimcIUZEgA8FOgrc737U2Vu4PycqICxZzTpLIE_MdURpYynWnVtBtpQEl7wKmqyV0ThUaZU58JhKLKkcWI48hAz8raVVhSTNWeq_P-2x9vsKywNZ1oEem451WNbI2G5kykUSEeYMPe4PO3PZonVwpW6DW0KLph_9OCEkSX7VH3_2FPl7dnqrBF6Dayvi8xWAqZ4lgWSR4NFDTRyg_SlypwrRYKR8fCT6OBJ5x-NvV0Fsr59dX_8F-_3d28XPMvj9gGwTtGmt0PzwvOwbjHVj4x207rB4uhBI5NM_9ycmheeS-ebzszeFlPojuu4X9AdHrEs8</recordid><startdate>20210809</startdate><enddate>20210809</enddate><creator>Tang, Ruijuan</creator><creator>Huang, Wuren</creator><creator>Guan, Jingmin</creator><creator>Liu, Qiuning</creator><creator>Beerntsen, Brenda T</creator><creator>Ling, Erjun</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-2101-2372</orcidid><orcidid>https://orcid.org/0000-0001-7193-3201</orcidid></search><sort><creationdate>20210809</creationdate><title>Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation</title><author>Tang, Ruijuan ; Huang, Wuren ; Guan, Jingmin ; Liu, Qiuning ; Beerntsen, Brenda T ; Ling, Erjun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c726t-a7983504e2fb141b79e19110451a3b5885025577b7b057834f6df59ea2c6e3a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amino acids</topic><topic>Animals</topic><topic>Antimicrobial Cationic Peptides - genetics</topic><topic>Antimicrobial peptides</topic><topic>Bacteria</topic><topic>Biochemical analysis</topic><topic>Biology and life sciences</topic><topic>Cellular signal transduction</topic><topic>Drosophila</topic><topic>Drosophila melanogaster - genetics</topic><topic>Drosophila melanogaster - metabolism</topic><topic>Drosophila Proteins - genetics</topic><topic>Drosophila Proteins - immunology</topic><topic>Drosophila Proteins - metabolism</topic><topic>Drosophila Proteins - physiology</topic><topic>Enzymes</topic><topic>Epistasis</topic><topic>Gene expression</topic><topic>Gene Expression - genetics</topic><topic>Gene Expression Regulation - genetics</topic><topic>Genetic aspects</topic><topic>Genetic regulation</topic><topic>Germfree</topic><topic>Gram-negative bacteria</topic><topic>Gram-positive bacteria</topic><topic>Histones</topic><topic>Histones - metabolism</topic><topic>Histones - physiology</topic><topic>Immune response</topic><topic>Immunity, Innate - genetics</topic><topic>Innate immunity</topic><topic>Insects</topic><topic>Kinases</topic><topic>Localization</topic><topic>Mammals</topic><topic>Medicine and Health Sciences</topic><topic>Microbiota</topic><topic>Mutants</topic><topic>NF-kappa B - genetics</topic><topic>NF-κB protein</topic><topic>Pathogens</topic><topic>Peptides</topic><topic>Phenotypes</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Signal Transduction - genetics</topic><topic>SUMO protein</topic><topic>Sumoylation - genetics</topic><topic>Toll-Like Receptors</topic><topic>Transcription factors</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tang, Ruijuan</creatorcontrib><creatorcontrib>Huang, Wuren</creatorcontrib><creatorcontrib>Guan, Jingmin</creatorcontrib><creatorcontrib>Liu, Qiuning</creatorcontrib><creatorcontrib>Beerntsen, Brenda T</creatorcontrib><creatorcontrib>Ling, Erjun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tang, Ruijuan</au><au>Huang, Wuren</au><au>Guan, Jingmin</au><au>Liu, Qiuning</au><au>Beerntsen, Brenda T</au><au>Ling, Erjun</au><au>Eleftherianos, Ioannis</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2021-08-09</date><risdate>2021</risdate><volume>17</volume><issue>8</issue><spage>e1009718</spage><epage>e1009718</epage><pages>e1009718-e1009718</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34370736</pmid><doi>10.1371/journal.pgen.1009718</doi><orcidid>https://orcid.org/0000-0002-2101-2372</orcidid><orcidid>https://orcid.org/0000-0001-7193-3201</orcidid><oa>free_for_read</oa></addata></record> |
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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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