Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin
The molecular basis of interindividual clinical variability upon infection with is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by infect...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2022-06, Vol.376 (6599), p.eabm6380-eabm6380 |
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| creator | Spaan, András N Neehus, Anna-Lena Laplantine, Emmanuel Staels, Frederik Ogishi, Masato Seeleuthner, Yoann Rapaport, Franck Lacey, Keenan A Van Nieuwenhove, Erika Chrabieh, Maya Hum, David Migaud, Mélanie Izmiryan, Araksya Lorenzo, Lazaro Kochetkov, Tatiana Heesterbeek, Dani A C Bardoel, Bart W DuMont, Ashley L Dobbs, Kerry Chardonnet, Solenne Heissel, Søren Baslan, Timour Zhang, Peng Yang, Rui Bogunovic, Dusan Wunderink, Herman F Haas, Pieter-Jan A Molina, Henrik Van Buggenhout, Griet Lyonnet, Stanislas Notarangelo, Luigi D Seppänen, Mikko R J Weil, Robert Seminario, Gisela Gomez-Tello, Héctor Wouters, Carine Mesdaghi, Mehrnaz Shahrooei, Mohammad Bossuyt, Xavier Sag, Erdal Topaloglu, Rezan Ozen, Seza Leavis, Helen L van Eijk, Maarten M J Bezrodnik, Liliana Blancas Galicia, Lizbeth Hovnanian, Alain Nassif, Aude Bader-Meunier, Brigitte Neven, Bénédicte Meyts, Isabelle Schrijvers, Rik Puel, Anne Bustamante, Jacinta Aksentijevich, Ivona Kastner, Daniel L Torres, Victor J Humblet-Baron, Stéphanie Liston, Adrian Abel, Laurent Boisson, Bertrand Casanova, Jean-Laurent |
| description | The molecular basis of interindividual clinical variability upon infection with
is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by
infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells. |
| doi_str_mv | 10.1126/science.abm6380 |
| format | Article |
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is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by
infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.</description><identifier>ISSN: 0036-8075</identifier><identifier>ISSN: 1095-9203</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.abm6380</identifier><identifier>PMID: 35587511</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Accumulation ; Age ; Antibodies ; Bacterial Toxins - immunology ; Caveolin ; Caveolin-1 ; Cell surface ; Chromosome 5 ; Chromosome aberrations ; Chromosome deletion ; Cri-du-Chat Syndrome - genetics ; Cri-du-Chat Syndrome - immunology ; Crosstalk ; Cytotoxicity ; Deletion ; Disease ; Endopeptidases - genetics ; Enrichment ; Fibroblasts ; Genomes ; Haploinsufficiency ; Haploinsufficiency - genetics ; Haploinsufficiency - immunology ; Hemolysin Proteins - immunology ; Heredity ; Heterozygotes ; Homogeneity ; Host-Pathogen Interactions - genetics ; Host-Pathogen Interactions - immunology ; Humans ; Immunity ; Immunity, Cellular - genetics ; Infectious diseases ; Leukocytes ; Life Sciences ; Lung diseases ; Lungs ; Lysine ; Metalloproteinase ; Mutation ; Necrosis ; Neutralizing ; NF-κB protein ; Patients ; Phenotypes ; Receptors ; Signaling ; Skin diseases ; Staphylococcal Infections - genetics ; Staphylococcal Infections - immunology ; Staphylococcal Infections - pathology ; Staphylococcus aureus ; Staphylococcus infections ; Toxicity ; Toxins ; Tumor necrosis factor ; Tumor necrosis factor-TNF ; Variability ; Virulence ; Virulence factors</subject><ispartof>Science (American Association for the Advancement of Science), 2022-06, Vol.376 (6599), p.eabm6380-eabm6380</ispartof><rights>Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-de4050e6d17995ff9a53b13726ae031c7f9d187f5fed540cbc5f9d900647a6403</citedby><cites>FETCH-LOGICAL-c385t-de4050e6d17995ff9a53b13726ae031c7f9d187f5fed540cbc5f9d900647a6403</cites><orcidid>0000-0002-9242-0170 ; 0000-0003-3062-1214 ; 0000-0002-6564-7214 ; 0000-0002-6426-8845 ; 0000-0002-8573-6820 ; 0000-0001-6553-2110 ; 0000-0002-3861-8864 ; 0000-0001-7188-4550 ; 0000-0003-2883-7868 ; 0000-0002-5916-4654 ; 0000-0001-6648-8684 ; 0000-0003-2421-7389 ; 0000-0002-7782-4169 ; 0000-0002-0280-1624 ; 0000-0002-9119-8635 ; 0000-0001-9491-0790 ; 0000-0001-7951-0967 ; 0000-0001-7016-6493 ; 0000-0003-4684-069X ; 0000-0002-7126-0489 ; 0000-0001-9733-3650 ; 0000-0001-8720-3684 ; 0000-0003-3412-7512 ; 0000-0001-8950-4990 ; 0000-0003-4427-2158 ; 0000-0001-5240-3555 ; 0000-0002-0277-8268 ; 0000-0002-6272-4085 ; 0000-0001-5235-0932 ; 0000-0001-6450-277X ; 0000-0001-9968-0074 ; 0000-0002-6358-6980 ; 0000-0002-3432-3137 ; 0000-0003-1214-0302 ; 0000-0002-6129-567X ; 0000-0002-8335-0262 ; 0000-0001-8476-8196 ; 0000-0001-9584-3198 ; 0000-0002-3439-2482 ; 0000-0001-5374-321X ; 0000-0002-4261-6220 ; 0000-0002-6423-0927 ; 0000-0003-2603-0323 ; 0000-0001-5657-9814 ; 0000-0003-3100-7275 ; 0000-0002-2407-0834 ; 0000-0002-6542-2656 ; 0000-0001-5981-7259</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,2871,2872,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35587511$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.sorbonne-universite.fr/hal-03810222$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Spaan, András N</creatorcontrib><creatorcontrib>Neehus, Anna-Lena</creatorcontrib><creatorcontrib>Laplantine, Emmanuel</creatorcontrib><creatorcontrib>Staels, Frederik</creatorcontrib><creatorcontrib>Ogishi, Masato</creatorcontrib><creatorcontrib>Seeleuthner, Yoann</creatorcontrib><creatorcontrib>Rapaport, Franck</creatorcontrib><creatorcontrib>Lacey, Keenan A</creatorcontrib><creatorcontrib>Van Nieuwenhove, Erika</creatorcontrib><creatorcontrib>Chrabieh, Maya</creatorcontrib><creatorcontrib>Hum, David</creatorcontrib><creatorcontrib>Migaud, Mélanie</creatorcontrib><creatorcontrib>Izmiryan, Araksya</creatorcontrib><creatorcontrib>Lorenzo, Lazaro</creatorcontrib><creatorcontrib>Kochetkov, Tatiana</creatorcontrib><creatorcontrib>Heesterbeek, Dani A C</creatorcontrib><creatorcontrib>Bardoel, Bart W</creatorcontrib><creatorcontrib>DuMont, Ashley L</creatorcontrib><creatorcontrib>Dobbs, Kerry</creatorcontrib><creatorcontrib>Chardonnet, Solenne</creatorcontrib><creatorcontrib>Heissel, Søren</creatorcontrib><creatorcontrib>Baslan, Timour</creatorcontrib><creatorcontrib>Zhang, Peng</creatorcontrib><creatorcontrib>Yang, Rui</creatorcontrib><creatorcontrib>Bogunovic, Dusan</creatorcontrib><creatorcontrib>Wunderink, Herman F</creatorcontrib><creatorcontrib>Haas, Pieter-Jan A</creatorcontrib><creatorcontrib>Molina, Henrik</creatorcontrib><creatorcontrib>Van Buggenhout, Griet</creatorcontrib><creatorcontrib>Lyonnet, Stanislas</creatorcontrib><creatorcontrib>Notarangelo, Luigi D</creatorcontrib><creatorcontrib>Seppänen, Mikko R J</creatorcontrib><creatorcontrib>Weil, Robert</creatorcontrib><creatorcontrib>Seminario, Gisela</creatorcontrib><creatorcontrib>Gomez-Tello, Héctor</creatorcontrib><creatorcontrib>Wouters, Carine</creatorcontrib><creatorcontrib>Mesdaghi, Mehrnaz</creatorcontrib><creatorcontrib>Shahrooei, Mohammad</creatorcontrib><creatorcontrib>Bossuyt, Xavier</creatorcontrib><creatorcontrib>Sag, Erdal</creatorcontrib><creatorcontrib>Topaloglu, Rezan</creatorcontrib><creatorcontrib>Ozen, Seza</creatorcontrib><creatorcontrib>Leavis, Helen L</creatorcontrib><creatorcontrib>van Eijk, Maarten M J</creatorcontrib><creatorcontrib>Bezrodnik, Liliana</creatorcontrib><creatorcontrib>Blancas Galicia, Lizbeth</creatorcontrib><creatorcontrib>Hovnanian, Alain</creatorcontrib><creatorcontrib>Nassif, Aude</creatorcontrib><creatorcontrib>Bader-Meunier, Brigitte</creatorcontrib><creatorcontrib>Neven, Bénédicte</creatorcontrib><creatorcontrib>Meyts, Isabelle</creatorcontrib><creatorcontrib>Schrijvers, Rik</creatorcontrib><creatorcontrib>Puel, Anne</creatorcontrib><creatorcontrib>Bustamante, Jacinta</creatorcontrib><creatorcontrib>Aksentijevich, Ivona</creatorcontrib><creatorcontrib>Kastner, Daniel L</creatorcontrib><creatorcontrib>Torres, Victor J</creatorcontrib><creatorcontrib>Humblet-Baron, Stéphanie</creatorcontrib><creatorcontrib>Liston, Adrian</creatorcontrib><creatorcontrib>Abel, Laurent</creatorcontrib><creatorcontrib>Boisson, Bertrand</creatorcontrib><creatorcontrib>Casanova, Jean-Laurent</creatorcontrib><title>Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>The molecular basis of interindividual clinical variability upon infection with
is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by
infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.</description><subject>Accumulation</subject><subject>Age</subject><subject>Antibodies</subject><subject>Bacterial Toxins - immunology</subject><subject>Caveolin</subject><subject>Caveolin-1</subject><subject>Cell surface</subject><subject>Chromosome 5</subject><subject>Chromosome aberrations</subject><subject>Chromosome deletion</subject><subject>Cri-du-Chat Syndrome - genetics</subject><subject>Cri-du-Chat Syndrome - immunology</subject><subject>Crosstalk</subject><subject>Cytotoxicity</subject><subject>Deletion</subject><subject>Disease</subject><subject>Endopeptidases - genetics</subject><subject>Enrichment</subject><subject>Fibroblasts</subject><subject>Genomes</subject><subject>Haploinsufficiency</subject><subject>Haploinsufficiency - genetics</subject><subject>Haploinsufficiency - immunology</subject><subject>Hemolysin Proteins - immunology</subject><subject>Heredity</subject><subject>Heterozygotes</subject><subject>Homogeneity</subject><subject>Host-Pathogen Interactions - genetics</subject><subject>Host-Pathogen Interactions - immunology</subject><subject>Humans</subject><subject>Immunity</subject><subject>Immunity, Cellular - genetics</subject><subject>Infectious diseases</subject><subject>Leukocytes</subject><subject>Life Sciences</subject><subject>Lung diseases</subject><subject>Lungs</subject><subject>Lysine</subject><subject>Metalloproteinase</subject><subject>Mutation</subject><subject>Necrosis</subject><subject>Neutralizing</subject><subject>NF-κB protein</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Receptors</subject><subject>Signaling</subject><subject>Skin diseases</subject><subject>Staphylococcal Infections - genetics</subject><subject>Staphylococcal Infections - immunology</subject><subject>Staphylococcal Infections - pathology</subject><subject>Staphylococcus aureus</subject><subject>Staphylococcus infections</subject><subject>Toxicity</subject><subject>Toxins</subject><subject>Tumor necrosis factor</subject><subject>Tumor necrosis factor-TNF</subject><subject>Variability</subject><subject>Virulence</subject><subject>Virulence 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OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin</title><author>Spaan, András N ; Neehus, Anna-Lena ; Laplantine, Emmanuel ; Staels, Frederik ; Ogishi, Masato ; Seeleuthner, Yoann ; Rapaport, Franck ; Lacey, Keenan A ; Van Nieuwenhove, Erika ; Chrabieh, Maya ; Hum, David ; Migaud, Mélanie ; Izmiryan, Araksya ; Lorenzo, Lazaro ; Kochetkov, Tatiana ; Heesterbeek, Dani A C ; Bardoel, Bart W ; DuMont, Ashley L ; Dobbs, Kerry ; Chardonnet, Solenne ; Heissel, Søren ; Baslan, Timour ; Zhang, Peng ; Yang, Rui ; Bogunovic, Dusan ; Wunderink, Herman F ; Haas, Pieter-Jan A ; Molina, Henrik ; Van Buggenhout, Griet ; Lyonnet, Stanislas ; Notarangelo, Luigi D ; Seppänen, Mikko R J ; Weil, Robert ; Seminario, Gisela ; Gomez-Tello, Héctor ; Wouters, Carine ; Mesdaghi, Mehrnaz ; Shahrooei, Mohammad ; Bossuyt, Xavier ; Sag, Erdal ; Topaloglu, Rezan ; Ozen, Seza ; Leavis, Helen L ; van Eijk, Maarten M J ; Bezrodnik, Liliana ; Blancas Galicia, Lizbeth ; Hovnanian, Alain ; Nassif, Aude ; Bader-Meunier, Brigitte ; Neven, Bénédicte ; Meyts, Isabelle ; Schrijvers, Rik ; Puel, Anne ; Bustamante, Jacinta ; Aksentijevich, Ivona ; Kastner, Daniel L ; Torres, Victor J ; Humblet-Baron, Stéphanie ; Liston, Adrian ; Abel, Laurent ; Boisson, Bertrand ; Casanova, Jean-Laurent</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-de4050e6d17995ff9a53b13726ae031c7f9d187f5fed540cbc5f9d900647a6403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Accumulation</topic><topic>Age</topic><topic>Antibodies</topic><topic>Bacterial Toxins - immunology</topic><topic>Caveolin</topic><topic>Caveolin-1</topic><topic>Cell surface</topic><topic>Chromosome 5</topic><topic>Chromosome aberrations</topic><topic>Chromosome deletion</topic><topic>Cri-du-Chat Syndrome - genetics</topic><topic>Cri-du-Chat Syndrome - immunology</topic><topic>Crosstalk</topic><topic>Cytotoxicity</topic><topic>Deletion</topic><topic>Disease</topic><topic>Endopeptidases - genetics</topic><topic>Enrichment</topic><topic>Fibroblasts</topic><topic>Genomes</topic><topic>Haploinsufficiency</topic><topic>Haploinsufficiency - genetics</topic><topic>Haploinsufficiency - immunology</topic><topic>Hemolysin Proteins - immunology</topic><topic>Heredity</topic><topic>Heterozygotes</topic><topic>Homogeneity</topic><topic>Host-Pathogen Interactions - genetics</topic><topic>Host-Pathogen Interactions - immunology</topic><topic>Humans</topic><topic>Immunity</topic><topic>Immunity, Cellular - genetics</topic><topic>Infectious diseases</topic><topic>Leukocytes</topic><topic>Life Sciences</topic><topic>Lung diseases</topic><topic>Lungs</topic><topic>Lysine</topic><topic>Metalloproteinase</topic><topic>Mutation</topic><topic>Necrosis</topic><topic>Neutralizing</topic><topic>NF-κB protein</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Receptors</topic><topic>Signaling</topic><topic>Skin diseases</topic><topic>Staphylococcal Infections - genetics</topic><topic>Staphylococcal Infections - immunology</topic><topic>Staphylococcal Infections - pathology</topic><topic>Staphylococcus aureus</topic><topic>Staphylococcus infections</topic><topic>Toxicity</topic><topic>Toxins</topic><topic>Tumor necrosis factor</topic><topic>Tumor necrosis factor-TNF</topic><topic>Variability</topic><topic>Virulence</topic><topic>Virulence factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Spaan, András N</creatorcontrib><creatorcontrib>Neehus, Anna-Lena</creatorcontrib><creatorcontrib>Laplantine, Emmanuel</creatorcontrib><creatorcontrib>Staels, Frederik</creatorcontrib><creatorcontrib>Ogishi, Masato</creatorcontrib><creatorcontrib>Seeleuthner, Yoann</creatorcontrib><creatorcontrib>Rapaport, 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A</au><au>Van Nieuwenhove, Erika</au><au>Chrabieh, Maya</au><au>Hum, David</au><au>Migaud, Mélanie</au><au>Izmiryan, Araksya</au><au>Lorenzo, Lazaro</au><au>Kochetkov, Tatiana</au><au>Heesterbeek, Dani A C</au><au>Bardoel, Bart W</au><au>DuMont, Ashley L</au><au>Dobbs, Kerry</au><au>Chardonnet, Solenne</au><au>Heissel, Søren</au><au>Baslan, Timour</au><au>Zhang, Peng</au><au>Yang, Rui</au><au>Bogunovic, Dusan</au><au>Wunderink, Herman F</au><au>Haas, Pieter-Jan A</au><au>Molina, Henrik</au><au>Van Buggenhout, Griet</au><au>Lyonnet, Stanislas</au><au>Notarangelo, Luigi D</au><au>Seppänen, Mikko R J</au><au>Weil, Robert</au><au>Seminario, Gisela</au><au>Gomez-Tello, Héctor</au><au>Wouters, Carine</au><au>Mesdaghi, Mehrnaz</au><au>Shahrooei, Mohammad</au><au>Bossuyt, Xavier</au><au>Sag, Erdal</au><au>Topaloglu, Rezan</au><au>Ozen, Seza</au><au>Leavis, Helen L</au><au>van Eijk, Maarten M J</au><au>Bezrodnik, Liliana</au><au>Blancas Galicia, Lizbeth</au><au>Hovnanian, Alain</au><au>Nassif, Aude</au><au>Bader-Meunier, Brigitte</au><au>Neven, Bénédicte</au><au>Meyts, Isabelle</au><au>Schrijvers, Rik</au><au>Puel, Anne</au><au>Bustamante, Jacinta</au><au>Aksentijevich, Ivona</au><au>Kastner, Daniel L</au><au>Torres, Victor J</au><au>Humblet-Baron, Stéphanie</au><au>Liston, Adrian</au><au>Abel, Laurent</au><au>Boisson, Bertrand</au><au>Casanova, Jean-Laurent</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2022-06-17</date><risdate>2022</risdate><volume>376</volume><issue>6599</issue><spage>eabm6380</spage><epage>eabm6380</epage><pages>eabm6380-eabm6380</pages><issn>0036-8075</issn><issn>1095-9203</issn><eissn>1095-9203</eissn><abstract>The molecular basis of interindividual clinical variability upon infection with
is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by
infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>35587511</pmid><doi>10.1126/science.abm6380</doi><orcidid>https://orcid.org/0000-0002-9242-0170</orcidid><orcidid>https://orcid.org/0000-0003-3062-1214</orcidid><orcidid>https://orcid.org/0000-0002-6564-7214</orcidid><orcidid>https://orcid.org/0000-0002-6426-8845</orcidid><orcidid>https://orcid.org/0000-0002-8573-6820</orcidid><orcidid>https://orcid.org/0000-0001-6553-2110</orcidid><orcidid>https://orcid.org/0000-0002-3861-8864</orcidid><orcidid>https://orcid.org/0000-0001-7188-4550</orcidid><orcidid>https://orcid.org/0000-0003-2883-7868</orcidid><orcidid>https://orcid.org/0000-0002-5916-4654</orcidid><orcidid>https://orcid.org/0000-0001-6648-8684</orcidid><orcidid>https://orcid.org/0000-0003-2421-7389</orcidid><orcidid>https://orcid.org/0000-0002-7782-4169</orcidid><orcidid>https://orcid.org/0000-0002-0280-1624</orcidid><orcidid>https://orcid.org/0000-0002-9119-8635</orcidid><orcidid>https://orcid.org/0000-0001-9491-0790</orcidid><orcidid>https://orcid.org/0000-0001-7951-0967</orcidid><orcidid>https://orcid.org/0000-0001-7016-6493</orcidid><orcidid>https://orcid.org/0000-0003-4684-069X</orcidid><orcidid>https://orcid.org/0000-0002-7126-0489</orcidid><orcidid>https://orcid.org/0000-0001-9733-3650</orcidid><orcidid>https://orcid.org/0000-0001-8720-3684</orcidid><orcidid>https://orcid.org/0000-0003-3412-7512</orcidid><orcidid>https://orcid.org/0000-0001-8950-4990</orcidid><orcidid>https://orcid.org/0000-0003-4427-2158</orcidid><orcidid>https://orcid.org/0000-0001-5240-3555</orcidid><orcidid>https://orcid.org/0000-0002-0277-8268</orcidid><orcidid>https://orcid.org/0000-0002-6272-4085</orcidid><orcidid>https://orcid.org/0000-0001-5235-0932</orcidid><orcidid>https://orcid.org/0000-0001-6450-277X</orcidid><orcidid>https://orcid.org/0000-0001-9968-0074</orcidid><orcidid>https://orcid.org/0000-0002-6358-6980</orcidid><orcidid>https://orcid.org/0000-0002-3432-3137</orcidid><orcidid>https://orcid.org/0000-0003-1214-0302</orcidid><orcidid>https://orcid.org/0000-0002-6129-567X</orcidid><orcidid>https://orcid.org/0000-0002-8335-0262</orcidid><orcidid>https://orcid.org/0000-0001-8476-8196</orcidid><orcidid>https://orcid.org/0000-0001-9584-3198</orcidid><orcidid>https://orcid.org/0000-0002-3439-2482</orcidid><orcidid>https://orcid.org/0000-0001-5374-321X</orcidid><orcidid>https://orcid.org/0000-0002-4261-6220</orcidid><orcidid>https://orcid.org/0000-0002-6423-0927</orcidid><orcidid>https://orcid.org/0000-0003-2603-0323</orcidid><orcidid>https://orcid.org/0000-0001-5657-9814</orcidid><orcidid>https://orcid.org/0000-0003-3100-7275</orcidid><orcidid>https://orcid.org/0000-0002-2407-0834</orcidid><orcidid>https://orcid.org/0000-0002-6542-2656</orcidid><orcidid>https://orcid.org/0000-0001-5981-7259</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2022-06, Vol.376 (6599), p.eabm6380-eabm6380 |
| issn | 0036-8075 1095-9203 1095-9203 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9233084 |
| source | MEDLINE; Science Magazine |
| subjects | Accumulation Age Antibodies Bacterial Toxins - immunology Caveolin Caveolin-1 Cell surface Chromosome 5 Chromosome aberrations Chromosome deletion Cri-du-Chat Syndrome - genetics Cri-du-Chat Syndrome - immunology Crosstalk Cytotoxicity Deletion Disease Endopeptidases - genetics Enrichment Fibroblasts Genomes Haploinsufficiency Haploinsufficiency - genetics Haploinsufficiency - immunology Hemolysin Proteins - immunology Heredity Heterozygotes Homogeneity Host-Pathogen Interactions - genetics Host-Pathogen Interactions - immunology Humans Immunity Immunity, Cellular - genetics Infectious diseases Leukocytes Life Sciences Lung diseases Lungs Lysine Metalloproteinase Mutation Necrosis Neutralizing NF-κB protein Patients Phenotypes Receptors Signaling Skin diseases Staphylococcal Infections - genetics Staphylococcal Infections - immunology Staphylococcal Infections - pathology Staphylococcus aureus Staphylococcus infections Toxicity Toxins Tumor necrosis factor Tumor necrosis factor-TNF Variability Virulence Virulence factors |
| title | Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin |
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