The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5
Flagellin is a wide-spread bacterial virulence factor sensed by the membrane-bound Toll-like receptor 5 (TLR5) and by the intracellular NAIP5/NLRC4 inflammasome receptor. TLR5 recognizes a conserved region within the D1 domain of flagellin, crucial for the interaction between subunits in the flagell...
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| description | Flagellin is a wide-spread bacterial virulence factor sensed by the membrane-bound Toll-like receptor 5 (TLR5) and by the intracellular NAIP5/NLRC4 inflammasome receptor. TLR5 recognizes a conserved region within the D1 domain of flagellin, crucial for the interaction between subunits in the flagellum and for bacterial motility. While it is known that a deletion of the D0 domain of flagellin, which lines the interior of flagella, also completely abrogates activation of TLR5, its functional role remains unknown. Using a protein fusion strategy, we propose a role for the D0 domain in the stabilization of an active dimeric signaling complex of flagellin-TLR5 at a 2:2 stoichiometric ratio. Alanine-scanning mutagenesis of flagellin revealed a previously unidentified region of flagellin, the C-terminal D0 domain, to play a crucial role in TLR5 activation. Interestingly, we show that TLR5 recognizes the same hydrophobic motif of the D0 domain of flagellin as the intracellular NAIP5/NLRC4 inflammasome receptor. Further, we show that residues within the D0 domain play a previously unrecognized role in the evasion of TLR5 recognition by Helicobacter pylori. These findings demonstrate that TLR5 is able to simultaneously sense several spatially separated sites of flagellin that are essential for its functionality, hindering bacterial evasion of immune recognition. Our findings significantly contribute to the understanding of the mechanism of TLR5 activation, which plays an important role in host defense against several pathogens, but also in several diseases, such as Crohn's disease, cystic fibrosis and rheumatoid arthritis. |
| doi_str_mv | 10.1371/journal.ppat.1006574 |
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TLR5 recognizes a conserved region within the D1 domain of flagellin, crucial for the interaction between subunits in the flagellum and for bacterial motility. While it is known that a deletion of the D0 domain of flagellin, which lines the interior of flagella, also completely abrogates activation of TLR5, its functional role remains unknown. Using a protein fusion strategy, we propose a role for the D0 domain in the stabilization of an active dimeric signaling complex of flagellin-TLR5 at a 2:2 stoichiometric ratio. Alanine-scanning mutagenesis of flagellin revealed a previously unidentified region of flagellin, the C-terminal D0 domain, to play a crucial role in TLR5 activation. Interestingly, we show that TLR5 recognizes the same hydrophobic motif of the D0 domain of flagellin as the intracellular NAIP5/NLRC4 inflammasome receptor. Further, we show that residues within the D0 domain play a previously unrecognized role in the evasion of TLR5 recognition by Helicobacter pylori. These findings demonstrate that TLR5 is able to simultaneously sense several spatially separated sites of flagellin that are essential for its functionality, hindering bacterial evasion of immune recognition. Our findings significantly contribute to the understanding of the mechanism of TLR5 activation, which plays an important role in host defense against several pathogens, but also in several diseases, such as Crohn's disease, cystic fibrosis and rheumatoid arthritis.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1006574</identifier><identifier>PMID: 28827825</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Alanine ; Animals ; Arthritis ; Bacteria ; Bacterial Infections - immunology ; Biology and Life Sciences ; Blotting, Western ; Cell Line ; Crohn's disease ; Cystic fibrosis ; Flagella ; Flagellin ; Flagellin - immunology ; Flagellin - metabolism ; Funding ; Fusion protein ; Helicobacter pylori ; Humans ; Hydrophobicity ; Immune system ; Immunity, Innate - immunology ; Immunology ; Immunoprecipitation ; Inflammasomes ; Intracellular ; Ligands ; Medicine and Health Sciences ; Mice ; Mutagenesis ; Pathogens ; Physical Sciences ; Proteins ; Recognition ; Rheumatoid arthritis ; Salmonella ; Scanning mutagenesis ; Synthetic biology ; TLR5 ; TLR5 protein ; Toll-Like Receptor 5 - immunology ; Toll-Like Receptor 5 - metabolism ; Toll-like receptors ; Virulence ; Virulence factors</subject><ispartof>PLoS pathogens, 2017-08, Vol.13 (8), p.e1006574-e1006574</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Forstneri? V, Ivi?ak-Kocjan K, Plaper T, Jerala R, Ben?ina M (2017) The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5. PLoS Pathog 13(8): e1006574. https://doi.org/10.1371/journal.ppat.1006574</rights><rights>2017 Forstnerič et al 2017 Forstnerič et al</rights><rights>2017 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Forstneri? V, Ivi?ak-Kocjan K, Plaper T, Jerala R, Ben?ina M (2017) The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5. PLoS Pathog 13(8): e1006574. https://doi.org/10.1371/journal.ppat.1006574</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c727t-5c5402f7345cbeae0cab12f1d539ed6a19b942fe297ef8363e47ea24432a9c353</citedby><cites>FETCH-LOGICAL-c727t-5c5402f7345cbeae0cab12f1d539ed6a19b942fe297ef8363e47ea24432a9c353</cites><orcidid>0000-0002-3644-9948 ; 0000-0003-3298-3913 ; 0000-0001-9452-7193 ; 0000-0002-2469-6335 ; 0000-0002-6337-5251</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/PMC5578693/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578693/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28827825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Forstnerič, Vida</creatorcontrib><creatorcontrib>Ivičak-Kocjan, Karolina</creatorcontrib><creatorcontrib>Plaper, Tjaša</creatorcontrib><creatorcontrib>Jerala, Roman</creatorcontrib><creatorcontrib>Benčina, Mojca</creatorcontrib><title>The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>Flagellin is a wide-spread bacterial virulence factor sensed by the membrane-bound Toll-like receptor 5 (TLR5) and by the intracellular NAIP5/NLRC4 inflammasome receptor. 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These findings demonstrate that TLR5 is able to simultaneously sense several spatially separated sites of flagellin that are essential for its functionality, hindering bacterial evasion of immune recognition. Our findings significantly contribute to the understanding of the mechanism of TLR5 activation, which plays an important role in host defense against several pathogens, but also in several diseases, such as Crohn's disease, cystic fibrosis and rheumatoid arthritis.</description><subject>Activation</subject><subject>Alanine</subject><subject>Animals</subject><subject>Arthritis</subject><subject>Bacteria</subject><subject>Bacterial Infections - immunology</subject><subject>Biology and Life Sciences</subject><subject>Blotting, Western</subject><subject>Cell Line</subject><subject>Crohn's disease</subject><subject>Cystic fibrosis</subject><subject>Flagella</subject><subject>Flagellin</subject><subject>Flagellin - immunology</subject><subject>Flagellin - metabolism</subject><subject>Funding</subject><subject>Fusion protein</subject><subject>Helicobacter pylori</subject><subject>Humans</subject><subject>Hydrophobicity</subject><subject>Immune system</subject><subject>Immunity, Innate - immunology</subject><subject>Immunology</subject><subject>Immunoprecipitation</subject><subject>Inflammasomes</subject><subject>Intracellular</subject><subject>Ligands</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mutagenesis</subject><subject>Pathogens</subject><subject>Physical Sciences</subject><subject>Proteins</subject><subject>Recognition</subject><subject>Rheumatoid arthritis</subject><subject>Salmonella</subject><subject>Scanning mutagenesis</subject><subject>Synthetic biology</subject><subject>TLR5</subject><subject>TLR5 protein</subject><subject>Toll-Like Receptor 5 - immunology</subject><subject>Toll-Like Receptor 5 - metabolism</subject><subject>Toll-like receptors</subject><subject>Virulence</subject><subject>Virulence factors</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVkltv0zAUgCMEYmPwDxBE4gUeWnyNk5dJU7lVmkCCIh4txznuXJy42O4E_x6nzaYV7QUlUmyf73zOOTpF8RyjOaYCv934XRiUm2-3Ks0xQhUX7EFxijmnM0EFe3hnfVI8iXGDEMMUV4-LE1LXRNSEnxY_VldQBu-g9KZMeb2YJQi9zebyHSo73ys7jDHj1Bqcy5v8Kp3stUrW70Mr71zp7M8sAg3b5EPJnxaPjHIRnk3fs-L7h_erxafZ5ZePy8XF5UwLItKMa84QMYIyrltQgLRqMTG447SBrlK4aRtGDJBGgKlpRYEJUIQxSlSjKadnxcuDd-t8lFNPosQNbVjGEcvE8kB0Xm3kNthehT_SKyv3Bz6spQrJagfSCM0B467FqGPMoJo0QFpe1cp0qOtEdp1Pt-3aHjoNQwrKHUmPI4O9kmt_LTkXddXQLHg9CYL_tYOYZG-jzn1VA_jd_r8xYRUlOKOv_kHvr26i1ioXYAfj8716lMoLjkhNEGaja34PlZ8Oeqv9AMbm86OEN0cJmUnwO63VLka5_Pb1P9jPxyw7sDr4GAOY295hJMexvilSjmMtp7HOaS_u9v026WaO6V_AHvFA</recordid><startdate>20170821</startdate><enddate>20170821</enddate><creator>Forstnerič, Vida</creator><creator>Ivičak-Kocjan, Karolina</creator><creator>Plaper, Tjaša</creator><creator>Jerala, Roman</creator><creator>Benčina, Mojca</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>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</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>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-3644-9948</orcidid><orcidid>https://orcid.org/0000-0003-3298-3913</orcidid><orcidid>https://orcid.org/0000-0001-9452-7193</orcidid><orcidid>https://orcid.org/0000-0002-2469-6335</orcidid><orcidid>https://orcid.org/0000-0002-6337-5251</orcidid></search><sort><creationdate>20170821</creationdate><title>The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5</title><author>Forstnerič, Vida ; Ivičak-Kocjan, Karolina ; Plaper, Tjaša ; Jerala, Roman ; Benčina, Mojca</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c727t-5c5402f7345cbeae0cab12f1d539ed6a19b942fe297ef8363e47ea24432a9c353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Activation</topic><topic>Alanine</topic><topic>Animals</topic><topic>Arthritis</topic><topic>Bacteria</topic><topic>Bacterial Infections - immunology</topic><topic>Biology and Life Sciences</topic><topic>Blotting, Western</topic><topic>Cell Line</topic><topic>Crohn's disease</topic><topic>Cystic fibrosis</topic><topic>Flagella</topic><topic>Flagellin</topic><topic>Flagellin - immunology</topic><topic>Flagellin - metabolism</topic><topic>Funding</topic><topic>Fusion protein</topic><topic>Helicobacter pylori</topic><topic>Humans</topic><topic>Hydrophobicity</topic><topic>Immune system</topic><topic>Immunity, Innate - immunology</topic><topic>Immunology</topic><topic>Immunoprecipitation</topic><topic>Inflammasomes</topic><topic>Intracellular</topic><topic>Ligands</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Mutagenesis</topic><topic>Pathogens</topic><topic>Physical Sciences</topic><topic>Proteins</topic><topic>Recognition</topic><topic>Rheumatoid arthritis</topic><topic>Salmonella</topic><topic>Scanning mutagenesis</topic><topic>Synthetic biology</topic><topic>TLR5</topic><topic>TLR5 protein</topic><topic>Toll-Like Receptor 5 - immunology</topic><topic>Toll-Like Receptor 5 - metabolism</topic><topic>Toll-like receptors</topic><topic>Virulence</topic><topic>Virulence factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Forstnerič, Vida</creatorcontrib><creatorcontrib>Ivičak-Kocjan, Karolina</creatorcontrib><creatorcontrib>Plaper, Tjaša</creatorcontrib><creatorcontrib>Jerala, Roman</creatorcontrib><creatorcontrib>Benčina, Mojca</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: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Complete (ProQuest Database)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</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 One Sustainability</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>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</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>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Biological Science Database</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Forstnerič, Vida</au><au>Ivičak-Kocjan, Karolina</au><au>Plaper, Tjaša</au><au>Jerala, Roman</au><au>Benčina, Mojca</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2017-08-21</date><risdate>2017</risdate><volume>13</volume><issue>8</issue><spage>e1006574</spage><epage>e1006574</epage><pages>e1006574-e1006574</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Flagellin is a wide-spread bacterial virulence factor sensed by the membrane-bound Toll-like receptor 5 (TLR5) and by the intracellular NAIP5/NLRC4 inflammasome receptor. TLR5 recognizes a conserved region within the D1 domain of flagellin, crucial for the interaction between subunits in the flagellum and for bacterial motility. While it is known that a deletion of the D0 domain of flagellin, which lines the interior of flagella, also completely abrogates activation of TLR5, its functional role remains unknown. Using a protein fusion strategy, we propose a role for the D0 domain in the stabilization of an active dimeric signaling complex of flagellin-TLR5 at a 2:2 stoichiometric ratio. Alanine-scanning mutagenesis of flagellin revealed a previously unidentified region of flagellin, the C-terminal D0 domain, to play a crucial role in TLR5 activation. Interestingly, we show that TLR5 recognizes the same hydrophobic motif of the D0 domain of flagellin as the intracellular NAIP5/NLRC4 inflammasome receptor. Further, we show that residues within the D0 domain play a previously unrecognized role in the evasion of TLR5 recognition by Helicobacter pylori. These findings demonstrate that TLR5 is able to simultaneously sense several spatially separated sites of flagellin that are essential for its functionality, hindering bacterial evasion of immune recognition. Our findings significantly contribute to the understanding of the mechanism of TLR5 activation, which plays an important role in host defense against several pathogens, but also in several diseases, such as Crohn's disease, cystic fibrosis and rheumatoid arthritis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28827825</pmid><doi>10.1371/journal.ppat.1006574</doi><orcidid>https://orcid.org/0000-0002-3644-9948</orcidid><orcidid>https://orcid.org/0000-0003-3298-3913</orcidid><orcidid>https://orcid.org/0000-0001-9452-7193</orcidid><orcidid>https://orcid.org/0000-0002-2469-6335</orcidid><orcidid>https://orcid.org/0000-0002-6337-5251</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Activation Alanine Animals Arthritis Bacteria Bacterial Infections - immunology Biology and Life Sciences Blotting, Western Cell Line Crohn's disease Cystic fibrosis Flagella Flagellin Flagellin - immunology Flagellin - metabolism Funding Fusion protein Helicobacter pylori Humans Hydrophobicity Immune system Immunity, Innate - immunology Immunology Immunoprecipitation Inflammasomes Intracellular Ligands Medicine and Health Sciences Mice Mutagenesis Pathogens Physical Sciences Proteins Recognition Rheumatoid arthritis Salmonella Scanning mutagenesis Synthetic biology TLR5 TLR5 protein Toll-Like Receptor 5 - immunology Toll-Like Receptor 5 - metabolism Toll-like receptors Virulence Virulence factors |
| title | The role of the C-terminal D0 domain of flagellin in activation of Toll like receptor 5 |
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