Two Human MYD88 Variants, S34Y and R98C, Interfere with MyD88-IRAK4-Myddosome Assembly

Innate immune receptors detect microbial pathogens and subsequently activate adaptive immune responses to combat pathogen invasion. MyD88 is a key adaptor molecule in both Toll-like receptor (TLR) and IL-1 receptor superfamily signaling pathways. This is illustrated by the fact that human individual...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Journal of biological chemistry 2011-01, Vol.286 (2), p.1341-1353
Hauptverfasser: George, Julie, Motshwene, Precious G., Wang, Hui, Kubarenko, Andriy V., Rautanen, Anna, Mills, Tara C., Hill, Adrian V.S., Gay, Nicholas J., Weber, Alexander N.R.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1353
container_issue 2
container_start_page 1341
container_title The Journal of biological chemistry
container_volume 286
creator George, Julie
Motshwene, Precious G.
Wang, Hui
Kubarenko, Andriy V.
Rautanen, Anna
Mills, Tara C.
Hill, Adrian V.S.
Gay, Nicholas J.
Weber, Alexander N.R.
description Innate immune receptors detect microbial pathogens and subsequently activate adaptive immune responses to combat pathogen invasion. MyD88 is a key adaptor molecule in both Toll-like receptor (TLR) and IL-1 receptor superfamily signaling pathways. This is illustrated by the fact that human individuals carrying rare, naturally occurring MYD88 point mutations suffer from reoccurring life-threatening infections. Here we analyzed the functional properties of six reported non-synonymous single nucleotide polymorphisms of MYD88 in an in vitro cellular system. Two variants found in the MyD88 death domain, S34Y and R98C, showed severely reduced NF-κB activation due to reduced homo-oligomerization and IRAK4 interaction. Structural modeling highlights Ser-34 and Arg-98 as residues important for the assembly of the Myddosome, a death domain (DD) post-receptor complex involving the DD of MyD88, IRAK4, and IRAK2 or IRAK1. Using S34Y and R98C as functional probes, our data show that MyD88 homo-oligomerization and IRAK4 interaction is modulated by the MyD88 TIR and IRAK4 kinase domain, demonstrating the functional importance of non-DD regions not observed in a recent Myddosome crystal structure. The differential interference of S34Y and R98C with some (IL-1 receptor, TLR2, TLR4, TLR5, and TLR7) but not all (TLR9) MyD88-dependent signaling pathways also suggests that receptor specificities exist at the level of the Myddosome. Given their detrimental effect on signaling, it is not surprising that our epidemiological analysis in several case-control studies confirms that S34Y and R98C are rare variants that may drastically contribute to susceptibility to infection in only few individuals.
doi_str_mv 10.1074/jbc.M110.159996
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3020742</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0021925820563230</els_id><sourcerecordid>835119352</sourcerecordid><originalsourceid>FETCH-LOGICAL-c466t-d0808a789c470ccc929dbecf843a4eb8423e8d440bb909b992005e6ea3317ced3</originalsourceid><addsrcrecordid>eNp1kUtP3DAUhS3UqkyBdXetd90QuI6dxN5UGk0fjMqoEi_BynKcGzBKYmpnQPPv62koahf1xrL8-Zzrcwh5x-CIQSWO72t7tGLbU6GUKnfIjIHkGS_Y9SsyA8hZpvJC7pK3Md5DWkKxN2Q3B1WWUMGMXF08eXqy7s1AVzefpaRXJjgzjPGQnnNxQ83Q0DMlF4d0OYwYWgxIn9x4R1ebRGfLs_l3ka02TeOj75HOY8S-7jb75HVruogHz_seufz65WJxkp3--LZczE8zK8pyzBqQIE0llRUVWGtVrpoabSsFNwJrKXKOshEC6lqBqpXKAQos0XDOKosN3yOfJt2Hdd1jY3EYg-n0Q3C9CRvtjdP_3gzuTt_6R80hT_nlSeDjs0DwP9cYR927aLHrzIB-HbVMUTLFiy15PJE2-BgDti8uDPS2DJ3K0Nsy9FRGevH-7-Fe-D_pJ-DDBLTGa3MbXNSX5zkwDsmSq9_jqYnAFOKjw6CjdTikr7uAdtSNd_-1_wXGW5_2</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>835119352</pqid></control><display><type>article</type><title>Two Human MYD88 Variants, S34Y and R98C, Interfere with MyD88-IRAK4-Myddosome Assembly</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>George, Julie ; Motshwene, Precious G. ; Wang, Hui ; Kubarenko, Andriy V. ; Rautanen, Anna ; Mills, Tara C. ; Hill, Adrian V.S. ; Gay, Nicholas J. ; Weber, Alexander N.R.</creator><creatorcontrib>George, Julie ; Motshwene, Precious G. ; Wang, Hui ; Kubarenko, Andriy V. ; Rautanen, Anna ; Mills, Tara C. ; Hill, Adrian V.S. ; Gay, Nicholas J. ; Weber, Alexander N.R.</creatorcontrib><description>Innate immune receptors detect microbial pathogens and subsequently activate adaptive immune responses to combat pathogen invasion. MyD88 is a key adaptor molecule in both Toll-like receptor (TLR) and IL-1 receptor superfamily signaling pathways. This is illustrated by the fact that human individuals carrying rare, naturally occurring MYD88 point mutations suffer from reoccurring life-threatening infections. Here we analyzed the functional properties of six reported non-synonymous single nucleotide polymorphisms of MYD88 in an in vitro cellular system. Two variants found in the MyD88 death domain, S34Y and R98C, showed severely reduced NF-κB activation due to reduced homo-oligomerization and IRAK4 interaction. Structural modeling highlights Ser-34 and Arg-98 as residues important for the assembly of the Myddosome, a death domain (DD) post-receptor complex involving the DD of MyD88, IRAK4, and IRAK2 or IRAK1. Using S34Y and R98C as functional probes, our data show that MyD88 homo-oligomerization and IRAK4 interaction is modulated by the MyD88 TIR and IRAK4 kinase domain, demonstrating the functional importance of non-DD regions not observed in a recent Myddosome crystal structure. The differential interference of S34Y and R98C with some (IL-1 receptor, TLR2, TLR4, TLR5, and TLR7) but not all (TLR9) MyD88-dependent signaling pathways also suggests that receptor specificities exist at the level of the Myddosome. Given their detrimental effect on signaling, it is not surprising that our epidemiological analysis in several case-control studies confirms that S34Y and R98C are rare variants that may drastically contribute to susceptibility to infection in only few individuals.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M110.159996</identifier><identifier>PMID: 20966070</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adaptor Proteins ; Computer Modeling ; Crystal Structure ; Crystallography ; Death Domain ; Genetic Polymorphism ; Genetic Predisposition to Disease ; Genetic Variation ; Genotype ; Humans ; Immunology ; Infections - genetics ; Infections - immunology ; Infections - metabolism ; Innate Immunity ; Interleukin Receptor-associated Kinase (IRAK) ; Interleukin-1 Receptor-Associated Kinases - immunology ; Interleukin-1 Receptor-Associated Kinases - metabolism ; Models, Chemical ; MyD88 ; Myeloid Differentiation Factor 88 - chemistry ; Myeloid Differentiation Factor 88 - genetics ; Myeloid Differentiation Factor 88 - metabolism ; Pattern Recognition Receptor ; Phenotype ; Polymorphism, Single Nucleotide ; Protein Structure, Tertiary ; Signal Transduction - immunology ; Structure-Activity Relationship</subject><ispartof>The Journal of biological chemistry, 2011-01, Vol.286 (2), p.1341-1353</ispartof><rights>2011 © 2011 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2011 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-d0808a789c470ccc929dbecf843a4eb8423e8d440bb909b992005e6ea3317ced3</citedby><cites>FETCH-LOGICAL-c466t-d0808a789c470ccc929dbecf843a4eb8423e8d440bb909b992005e6ea3317ced3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020742/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020742/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20966070$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>George, Julie</creatorcontrib><creatorcontrib>Motshwene, Precious G.</creatorcontrib><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Kubarenko, Andriy V.</creatorcontrib><creatorcontrib>Rautanen, Anna</creatorcontrib><creatorcontrib>Mills, Tara C.</creatorcontrib><creatorcontrib>Hill, Adrian V.S.</creatorcontrib><creatorcontrib>Gay, Nicholas J.</creatorcontrib><creatorcontrib>Weber, Alexander N.R.</creatorcontrib><title>Two Human MYD88 Variants, S34Y and R98C, Interfere with MyD88-IRAK4-Myddosome Assembly</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Innate immune receptors detect microbial pathogens and subsequently activate adaptive immune responses to combat pathogen invasion. MyD88 is a key adaptor molecule in both Toll-like receptor (TLR) and IL-1 receptor superfamily signaling pathways. This is illustrated by the fact that human individuals carrying rare, naturally occurring MYD88 point mutations suffer from reoccurring life-threatening infections. Here we analyzed the functional properties of six reported non-synonymous single nucleotide polymorphisms of MYD88 in an in vitro cellular system. Two variants found in the MyD88 death domain, S34Y and R98C, showed severely reduced NF-κB activation due to reduced homo-oligomerization and IRAK4 interaction. Structural modeling highlights Ser-34 and Arg-98 as residues important for the assembly of the Myddosome, a death domain (DD) post-receptor complex involving the DD of MyD88, IRAK4, and IRAK2 or IRAK1. Using S34Y and R98C as functional probes, our data show that MyD88 homo-oligomerization and IRAK4 interaction is modulated by the MyD88 TIR and IRAK4 kinase domain, demonstrating the functional importance of non-DD regions not observed in a recent Myddosome crystal structure. The differential interference of S34Y and R98C with some (IL-1 receptor, TLR2, TLR4, TLR5, and TLR7) but not all (TLR9) MyD88-dependent signaling pathways also suggests that receptor specificities exist at the level of the Myddosome. Given their detrimental effect on signaling, it is not surprising that our epidemiological analysis in several case-control studies confirms that S34Y and R98C are rare variants that may drastically contribute to susceptibility to infection in only few individuals.</description><subject>Adaptor Proteins</subject><subject>Computer Modeling</subject><subject>Crystal Structure</subject><subject>Crystallography</subject><subject>Death Domain</subject><subject>Genetic Polymorphism</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Variation</subject><subject>Genotype</subject><subject>Humans</subject><subject>Immunology</subject><subject>Infections - genetics</subject><subject>Infections - immunology</subject><subject>Infections - metabolism</subject><subject>Innate Immunity</subject><subject>Interleukin Receptor-associated Kinase (IRAK)</subject><subject>Interleukin-1 Receptor-Associated Kinases - immunology</subject><subject>Interleukin-1 Receptor-Associated Kinases - metabolism</subject><subject>Models, Chemical</subject><subject>MyD88</subject><subject>Myeloid Differentiation Factor 88 - chemistry</subject><subject>Myeloid Differentiation Factor 88 - genetics</subject><subject>Myeloid Differentiation Factor 88 - metabolism</subject><subject>Pattern Recognition Receptor</subject><subject>Phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Structure, Tertiary</subject><subject>Signal Transduction - immunology</subject><subject>Structure-Activity Relationship</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUtP3DAUhS3UqkyBdXetd90QuI6dxN5UGk0fjMqoEi_BynKcGzBKYmpnQPPv62koahf1xrL8-Zzrcwh5x-CIQSWO72t7tGLbU6GUKnfIjIHkGS_Y9SsyA8hZpvJC7pK3Md5DWkKxN2Q3B1WWUMGMXF08eXqy7s1AVzefpaRXJjgzjPGQnnNxQ83Q0DMlF4d0OYwYWgxIn9x4R1ebRGfLs_l3ka02TeOj75HOY8S-7jb75HVruogHz_seufz65WJxkp3--LZczE8zK8pyzBqQIE0llRUVWGtVrpoabSsFNwJrKXKOshEC6lqBqpXKAQos0XDOKosN3yOfJt2Hdd1jY3EYg-n0Q3C9CRvtjdP_3gzuTt_6R80hT_nlSeDjs0DwP9cYR927aLHrzIB-HbVMUTLFiy15PJE2-BgDti8uDPS2DJ3K0Nsy9FRGevH-7-Fe-D_pJ-DDBLTGa3MbXNSX5zkwDsmSq9_jqYnAFOKjw6CjdTikr7uAdtSNd_-1_wXGW5_2</recordid><startdate>20110114</startdate><enddate>20110114</enddate><creator>George, Julie</creator><creator>Motshwene, Precious G.</creator><creator>Wang, Hui</creator><creator>Kubarenko, Andriy V.</creator><creator>Rautanen, Anna</creator><creator>Mills, Tara C.</creator><creator>Hill, Adrian V.S.</creator><creator>Gay, Nicholas J.</creator><creator>Weber, Alexander N.R.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110114</creationdate><title>Two Human MYD88 Variants, S34Y and R98C, Interfere with MyD88-IRAK4-Myddosome Assembly</title><author>George, Julie ; Motshwene, Precious G. ; Wang, Hui ; Kubarenko, Andriy V. ; Rautanen, Anna ; Mills, Tara C. ; Hill, Adrian V.S. ; Gay, Nicholas J. ; Weber, Alexander N.R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c466t-d0808a789c470ccc929dbecf843a4eb8423e8d440bb909b992005e6ea3317ced3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adaptor Proteins</topic><topic>Computer Modeling</topic><topic>Crystal Structure</topic><topic>Crystallography</topic><topic>Death Domain</topic><topic>Genetic Polymorphism</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic Variation</topic><topic>Genotype</topic><topic>Humans</topic><topic>Immunology</topic><topic>Infections - genetics</topic><topic>Infections - immunology</topic><topic>Infections - metabolism</topic><topic>Innate Immunity</topic><topic>Interleukin Receptor-associated Kinase (IRAK)</topic><topic>Interleukin-1 Receptor-Associated Kinases - immunology</topic><topic>Interleukin-1 Receptor-Associated Kinases - metabolism</topic><topic>Models, Chemical</topic><topic>MyD88</topic><topic>Myeloid Differentiation Factor 88 - chemistry</topic><topic>Myeloid Differentiation Factor 88 - genetics</topic><topic>Myeloid Differentiation Factor 88 - metabolism</topic><topic>Pattern Recognition Receptor</topic><topic>Phenotype</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein Structure, Tertiary</topic><topic>Signal Transduction - immunology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>George, Julie</creatorcontrib><creatorcontrib>Motshwene, Precious G.</creatorcontrib><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Kubarenko, Andriy V.</creatorcontrib><creatorcontrib>Rautanen, Anna</creatorcontrib><creatorcontrib>Mills, Tara C.</creatorcontrib><creatorcontrib>Hill, Adrian V.S.</creatorcontrib><creatorcontrib>Gay, Nicholas J.</creatorcontrib><creatorcontrib>Weber, Alexander N.R.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>George, Julie</au><au>Motshwene, Precious G.</au><au>Wang, Hui</au><au>Kubarenko, Andriy V.</au><au>Rautanen, Anna</au><au>Mills, Tara C.</au><au>Hill, Adrian V.S.</au><au>Gay, Nicholas J.</au><au>Weber, Alexander N.R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Two Human MYD88 Variants, S34Y and R98C, Interfere with MyD88-IRAK4-Myddosome Assembly</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2011-01-14</date><risdate>2011</risdate><volume>286</volume><issue>2</issue><spage>1341</spage><epage>1353</epage><pages>1341-1353</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Innate immune receptors detect microbial pathogens and subsequently activate adaptive immune responses to combat pathogen invasion. MyD88 is a key adaptor molecule in both Toll-like receptor (TLR) and IL-1 receptor superfamily signaling pathways. This is illustrated by the fact that human individuals carrying rare, naturally occurring MYD88 point mutations suffer from reoccurring life-threatening infections. Here we analyzed the functional properties of six reported non-synonymous single nucleotide polymorphisms of MYD88 in an in vitro cellular system. Two variants found in the MyD88 death domain, S34Y and R98C, showed severely reduced NF-κB activation due to reduced homo-oligomerization and IRAK4 interaction. Structural modeling highlights Ser-34 and Arg-98 as residues important for the assembly of the Myddosome, a death domain (DD) post-receptor complex involving the DD of MyD88, IRAK4, and IRAK2 or IRAK1. Using S34Y and R98C as functional probes, our data show that MyD88 homo-oligomerization and IRAK4 interaction is modulated by the MyD88 TIR and IRAK4 kinase domain, demonstrating the functional importance of non-DD regions not observed in a recent Myddosome crystal structure. The differential interference of S34Y and R98C with some (IL-1 receptor, TLR2, TLR4, TLR5, and TLR7) but not all (TLR9) MyD88-dependent signaling pathways also suggests that receptor specificities exist at the level of the Myddosome. Given their detrimental effect on signaling, it is not surprising that our epidemiological analysis in several case-control studies confirms that S34Y and R98C are rare variants that may drastically contribute to susceptibility to infection in only few individuals.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20966070</pmid><doi>10.1074/jbc.M110.159996</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0021-9258
ispartof The Journal of biological chemistry, 2011-01, Vol.286 (2), p.1341-1353
issn 0021-9258
1083-351X
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3020742
source MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection
subjects Adaptor Proteins
Computer Modeling
Crystal Structure
Crystallography
Death Domain
Genetic Polymorphism
Genetic Predisposition to Disease
Genetic Variation
Genotype
Humans
Immunology
Infections - genetics
Infections - immunology
Infections - metabolism
Innate Immunity
Interleukin Receptor-associated Kinase (IRAK)
Interleukin-1 Receptor-Associated Kinases - immunology
Interleukin-1 Receptor-Associated Kinases - metabolism
Models, Chemical
MyD88
Myeloid Differentiation Factor 88 - chemistry
Myeloid Differentiation Factor 88 - genetics
Myeloid Differentiation Factor 88 - metabolism
Pattern Recognition Receptor
Phenotype
Polymorphism, Single Nucleotide
Protein Structure, Tertiary
Signal Transduction - immunology
Structure-Activity Relationship
title Two Human MYD88 Variants, S34Y and R98C, Interfere with MyD88-IRAK4-Myddosome Assembly
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T12%3A53%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Two%20Human%20MYD88%20Variants,%20S34Y%20and%20R98C,%20Interfere%20with%20MyD88-IRAK4-Myddosome%20Assembly&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=George,%20Julie&rft.date=2011-01-14&rft.volume=286&rft.issue=2&rft.spage=1341&rft.epage=1353&rft.pages=1341-1353&rft.issn=0021-9258&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.M110.159996&rft_dat=%3Cproquest_pubme%3E835119352%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=835119352&rft_id=info:pmid/20966070&rft_els_id=S0021925820563230&rfr_iscdi=true