Mutation in KARS: A novel mechanism for severe anaphylaxis

Background: Anaphylaxis is a severe allergic reaction that can be lethal if not treated adequately. The underlying molecular mechanisms responsible for the severity are mostly unknown. Objective: This study is based on a clinical case of a patient with extremely severe anaphylaxis to paper wasp veno...

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Authors: Ribó, Pau, Guo, Yanru, Aranda Moratalla, Juan, Ainsua Enrich, Erola, Navinés Ferrer, Arnau, Guerrero, Mario, Pascal i Capdevila, Mariona, Cruz, Cinthia de la, Orozco López, Modesto, Muñoz-Cano, Rosa, Martín Andorrà, Margarita
Format: article
Status:Versión aceptada para publicación
Publication Date:2020
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/228017
Online Access:https://hdl.handle.net/2445/228017
Access Level:Open access
Keyword:Mastòcits
Anafilaxi
Genètica
Mast cells
Anaphylaxis
Genetics
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spelling Mutation in KARS: A novel mechanism for severe anaphylaxisRibó, PauGuo, YanruAranda Moratalla, JuanAinsua Enrich, ErolaNavinés Ferrer, ArnauGuerrero, MarioPascal i Capdevila, MarionaCruz, Cinthia de laOrozco López, ModestoMuñoz-Cano, RosaMartín Andorrà, MargaritaMastòcitsAnafilaxiGenèticaMast cellsAnaphylaxisGeneticsBackground: Anaphylaxis is a severe allergic reaction that can be lethal if not treated adequately. The underlying molecular mechanisms responsible for the severity are mostly unknown. Objective: This study is based on a clinical case of a patient with extremely severe anaphylaxis to paper wasp venom. This patient has a mutation in the KARS gene, which encodes lysyl-tRNA synthetase (LysRS), a moonlight protein with a canonical function in protein synthesis and a noncanonical function in antigen dependent-FcεRI activation in mast cells. In this study, the objective was to characterize the mutation at the molecular level. Methods: Analysis of the KARS mutation was carried out using biochemical and functional approaches, cell transfection, Western blot, confocal microscopy, cell degranulation, prostaglandin D2 secretion, and proteases gene transcription. Structural analysis using molecular dynamics simulations and well-tempered metadynamics was also performed. Results: The mutation found, P542R (proline was replaced by arginine at aminoacid 542), affects the location of the protein as we show in biochemical and structural analyses. The mutation resembles active LysRS and causes a constitutive activation of the microphthalmia transcription factor, which is involved in critical mast cell functions such as synthesis of mediators and granule biogenesis. Moreover, the structural analysis provides insights into how LysRS works in mast cell activation. Conclusions: A link between the aberrant LysRS-P542R function and mast cell-exacerbated activation with increase in proinflammatory mediator release after antigen-IgE-dependent response could be established.Mosby2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/228017Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1016/j.jaci.2020.12.637Journal of Allergy and Clinical Immunology, 2021, vol. 147, num.5, p. 1855-1864.e9.https://doi.org/10.1016/j.jaci.2020.12.637cc-by-nc-nd (c) American Academy of Allergy, Asthma and Immunology, 2021http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2280172026-05-27T06:46:51Z
dc.title.none.fl_str_mv Mutation in KARS: A novel mechanism for severe anaphylaxis
title Mutation in KARS: A novel mechanism for severe anaphylaxis
spellingShingle Mutation in KARS: A novel mechanism for severe anaphylaxis
Ribó, Pau
Mastòcits
Anafilaxi
Genètica
Mast cells
Anaphylaxis
Genetics
title_short Mutation in KARS: A novel mechanism for severe anaphylaxis
title_full Mutation in KARS: A novel mechanism for severe anaphylaxis
title_fullStr Mutation in KARS: A novel mechanism for severe anaphylaxis
title_full_unstemmed Mutation in KARS: A novel mechanism for severe anaphylaxis
title_sort Mutation in KARS: A novel mechanism for severe anaphylaxis
dc.creator.none.fl_str_mv Ribó, Pau
Guo, Yanru
Aranda Moratalla, Juan
Ainsua Enrich, Erola
Navinés Ferrer, Arnau
Guerrero, Mario
Pascal i Capdevila, Mariona
Cruz, Cinthia de la
Orozco López, Modesto
Muñoz-Cano, Rosa
Martín Andorrà, Margarita
author Ribó, Pau
author_facet Ribó, Pau
Guo, Yanru
Aranda Moratalla, Juan
Ainsua Enrich, Erola
Navinés Ferrer, Arnau
Guerrero, Mario
Pascal i Capdevila, Mariona
Cruz, Cinthia de la
Orozco López, Modesto
Muñoz-Cano, Rosa
Martín Andorrà, Margarita
author_role author
author2 Guo, Yanru
Aranda Moratalla, Juan
Ainsua Enrich, Erola
Navinés Ferrer, Arnau
Guerrero, Mario
Pascal i Capdevila, Mariona
Cruz, Cinthia de la
Orozco López, Modesto
Muñoz-Cano, Rosa
Martín Andorrà, Margarita
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mastòcits
Anafilaxi
Genètica
Mast cells
Anaphylaxis
Genetics
topic Mastòcits
Anafilaxi
Genètica
Mast cells
Anaphylaxis
Genetics
description Background: Anaphylaxis is a severe allergic reaction that can be lethal if not treated adequately. The underlying molecular mechanisms responsible for the severity are mostly unknown. Objective: This study is based on a clinical case of a patient with extremely severe anaphylaxis to paper wasp venom. This patient has a mutation in the KARS gene, which encodes lysyl-tRNA synthetase (LysRS), a moonlight protein with a canonical function in protein synthesis and a noncanonical function in antigen dependent-FcεRI activation in mast cells. In this study, the objective was to characterize the mutation at the molecular level. Methods: Analysis of the KARS mutation was carried out using biochemical and functional approaches, cell transfection, Western blot, confocal microscopy, cell degranulation, prostaglandin D2 secretion, and proteases gene transcription. Structural analysis using molecular dynamics simulations and well-tempered metadynamics was also performed. Results: The mutation found, P542R (proline was replaced by arginine at aminoacid 542), affects the location of the protein as we show in biochemical and structural analyses. The mutation resembles active LysRS and causes a constitutive activation of the microphthalmia transcription factor, which is involved in critical mast cell functions such as synthesis of mediators and granule biogenesis. Moreover, the structural analysis provides insights into how LysRS works in mast cell activation. Conclusions: A link between the aberrant LysRS-P542R function and mast cell-exacerbated activation with increase in proinflammatory mediator release after antigen-IgE-dependent response could be established.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/228017
url https://hdl.handle.net/2445/228017
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1016/j.jaci.2020.12.637
Journal of Allergy and Clinical Immunology, 2021, vol. 147, num.5, p. 1855-1864.e9.
https://doi.org/10.1016/j.jaci.2020.12.637
dc.rights.none.fl_str_mv cc-by-nc-nd (c) American Academy of Allergy, Asthma and Immunology, 2021
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) American Academy of Allergy, Asthma and Immunology, 2021
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Mosby
publisher.none.fl_str_mv Mosby
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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