Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β

Autores
Luksch, Hella; Romanowski, Michael J.; Chara, Osvaldo; Tuengler, Victoria; Caffarena, Ernesto Raúl; Heymann, Michael C.; Lohse, Peter; Aksentijevich, Ivona; Remmers, Elaine F.; Flecks, Silvana; Quoos, Nadine; Gramatté, Johannes; Petzold, Cathleen; Hofmann, Sigrun R.; Winkler, Stefan; Pessler, Frank; Kallinich, Tilmann; Ganser, Gerd; Nimtz-Talaska, Antje; Baumann, Ulrich; Runde, Volker; Grimbacher, Bodo; Birmelin, Jennifer; Gahr, Manfred; Roesler, Joachim; Rösen-Wolff, Angela
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. In- flammation is often mediated by enzymatic activation of interleukin (IL)-1β and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1β releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation.
Fil: Luksch, Hella. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Romanowski, Michael J.. Sunesis Pharmaceuticals. Department of Structural Biology; Estados Unidos
Fil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Technische Universitat Dresden. Center for Information Services and High-Performance Computing; Alemania
Fil: Tuengler, Victoria. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Caffarena, Ernesto Raúl. Escola Nacional de Saude Publica Sergio Arouca. Fundación Oswaldo Cruz; Brasil
Fil: Heymann, Michael C.. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Lohse, Peter. Ludwig-Maximilians-Universit; Alemania
Fil: Aksentijevich, Ivona. Inflammatory Disease Section; Estados Unidos
Fil: Remmers, Elaine F.. Inflammatory Disease Section; Estados Unidos
Fil: Flecks, Silvana. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Quoos, Nadine. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Gramatté, Johannes. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Petzold, Cathleen. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Hofmann, Sigrun R.. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Winkler, Stefan. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Pessler, Frank. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania. Helmholtz Centre for Infection Research; Alemania
Fil: Kallinich, Tilmann. Universität zu Berlin; Alemania
Fil: Ganser, Gerd. Sendenhorst. St. Josef-Stift; Alemania
Fil: Nimtz-Talaska, Antje. Kinderrheumatologie; Alemania
Fil: Baumann, Ulrich. Hannover Medical School; Alemania
Fil: Runde, Volker. Wilhelm-Anton-Hospital; Alemania
Fil: Grimbacher, Bodo. University Hospital Freiburg; Alemania
Fil: Birmelin, Jennifer. University Hospital Freiburg; Alemania
Fil: Gahr, Manfred. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Roesler, Joachim. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Rösen-Wolff, Angela. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Materia
Autoinflammatory
Rheumatic
Procaspase
Heterozygous
Cytokine
Homozygous
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/24124
Acceder
id CONICETDig_2dad795a90280078533c181a4f25ee66
oai_identifier_str oai:ri.conicet.gov.ar:11336/24124
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1βLuksch, HellaRomanowski, Michael J.Chara, OsvaldoTuengler, VictoriaCaffarena, Ernesto RaúlHeymann, Michael C.Lohse, PeterAksentijevich, IvonaRemmers, Elaine F.Flecks, SilvanaQuoos, NadineGramatté, JohannesPetzold, CathleenHofmann, Sigrun R.Winkler, StefanPessler, FrankKallinich, TilmannGanser, GerdNimtz-Talaska, AntjeBaumann, UlrichRunde, VolkerGrimbacher, BodoBirmelin, JenniferGahr, ManfredRoesler, JoachimRösen-Wolff, AngelaAutoinflammatoryRheumaticProcaspaseHeterozygousCytokineHomozygoushttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. In- flammation is often mediated by enzymatic activation of interleukin (IL)-1β and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1β releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation.Fil: Luksch, Hella. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Romanowski, Michael J.. Sunesis Pharmaceuticals. Department of Structural Biology; Estados UnidosFil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Technische Universitat Dresden. Center for Information Services and High-Performance Computing; AlemaniaFil: Tuengler, Victoria. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Caffarena, Ernesto Raúl. Escola Nacional de Saude Publica Sergio Arouca. Fundación Oswaldo Cruz; BrasilFil: Heymann, Michael C.. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Lohse, Peter. Ludwig-Maximilians-Universit; AlemaniaFil: Aksentijevich, Ivona. Inflammatory Disease Section; Estados UnidosFil: Remmers, Elaine F.. Inflammatory Disease Section; Estados UnidosFil: Flecks, Silvana. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Quoos, Nadine. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Gramatté, Johannes. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Petzold, Cathleen. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Hofmann, Sigrun R.. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Winkler, Stefan. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Pessler, Frank. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania. Helmholtz Centre for Infection Research; AlemaniaFil: Kallinich, Tilmann. Universität zu Berlin; AlemaniaFil: Ganser, Gerd. Sendenhorst. St. Josef-Stift; AlemaniaFil: Nimtz-Talaska, Antje. Kinderrheumatologie; AlemaniaFil: Baumann, Ulrich. Hannover Medical School; AlemaniaFil: Runde, Volker. Wilhelm-Anton-Hospital; AlemaniaFil: Grimbacher, Bodo. University Hospital Freiburg; AlemaniaFil: Birmelin, Jennifer. University Hospital Freiburg; AlemaniaFil: Gahr, Manfred. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Roesler, Joachim. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaFil: Rösen-Wolff, Angela. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; AlemaniaWiley-liss, Div John Wiley & Sons Inc2013-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/24124Luksch, Hella; Romanowski, Michael J.; Chara, Osvaldo; Tuengler, Victoria; Caffarena, Ernesto Raúl; et al.; Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β; Wiley-liss, Div John Wiley & Sons Inc; Human Mutation; 34; 1; 1-2013; 122-1311059-7794CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/humu.22169/abstractinfo:eu-repo/semantics/altIdentifier/doi/10.1002/humu.22169info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:47:03Zoai:ri.conicet.gov.ar:11336/24124instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:47:03.777CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
title Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
spellingShingle Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
Luksch, Hella
Autoinflammatory
Rheumatic
Procaspase
Heterozygous
Cytokine
Homozygous
title_short Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
title_full Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
title_fullStr Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
title_full_unstemmed Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
title_sort Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β
dc.creator.none.fl_str_mv Luksch, Hella
Romanowski, Michael J.
Chara, Osvaldo
Tuengler, Victoria
Caffarena, Ernesto Raúl
Heymann, Michael C.
Lohse, Peter
Aksentijevich, Ivona
Remmers, Elaine F.
Flecks, Silvana
Quoos, Nadine
Gramatté, Johannes
Petzold, Cathleen
Hofmann, Sigrun R.
Winkler, Stefan
Pessler, Frank
Kallinich, Tilmann
Ganser, Gerd
Nimtz-Talaska, Antje
Baumann, Ulrich
Runde, Volker
Grimbacher, Bodo
Birmelin, Jennifer
Gahr, Manfred
Roesler, Joachim
Rösen-Wolff, Angela
author Luksch, Hella
author_facet Luksch, Hella
Romanowski, Michael J.
Chara, Osvaldo
Tuengler, Victoria
Caffarena, Ernesto Raúl
Heymann, Michael C.
Lohse, Peter
Aksentijevich, Ivona
Remmers, Elaine F.
Flecks, Silvana
Quoos, Nadine
Gramatté, Johannes
Petzold, Cathleen
Hofmann, Sigrun R.
Winkler, Stefan
Pessler, Frank
Kallinich, Tilmann
Ganser, Gerd
Nimtz-Talaska, Antje
Baumann, Ulrich
Runde, Volker
Grimbacher, Bodo
Birmelin, Jennifer
Gahr, Manfred
Roesler, Joachim
Rösen-Wolff, Angela
author_role author
author2 Romanowski, Michael J.
Chara, Osvaldo
Tuengler, Victoria
Caffarena, Ernesto Raúl
Heymann, Michael C.
Lohse, Peter
Aksentijevich, Ivona
Remmers, Elaine F.
Flecks, Silvana
Quoos, Nadine
Gramatté, Johannes
Petzold, Cathleen
Hofmann, Sigrun R.
Winkler, Stefan
Pessler, Frank
Kallinich, Tilmann
Ganser, Gerd
Nimtz-Talaska, Antje
Baumann, Ulrich
Runde, Volker
Grimbacher, Bodo
Birmelin, Jennifer
Gahr, Manfred
Roesler, Joachim
Rösen-Wolff, Angela
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Autoinflammatory
Rheumatic
Procaspase
Heterozygous
Cytokine
Homozygous
topic Autoinflammatory
Rheumatic
Procaspase
Heterozygous
Cytokine
Homozygous
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. In- flammation is often mediated by enzymatic activation of interleukin (IL)-1β and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1β releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation.
Fil: Luksch, Hella. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Romanowski, Michael J.. Sunesis Pharmaceuticals. Department of Structural Biology; Estados Unidos
Fil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Technische Universitat Dresden. Center for Information Services and High-Performance Computing; Alemania
Fil: Tuengler, Victoria. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Caffarena, Ernesto Raúl. Escola Nacional de Saude Publica Sergio Arouca. Fundación Oswaldo Cruz; Brasil
Fil: Heymann, Michael C.. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Lohse, Peter. Ludwig-Maximilians-Universit; Alemania
Fil: Aksentijevich, Ivona. Inflammatory Disease Section; Estados Unidos
Fil: Remmers, Elaine F.. Inflammatory Disease Section; Estados Unidos
Fil: Flecks, Silvana. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Quoos, Nadine. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Gramatté, Johannes. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Petzold, Cathleen. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Hofmann, Sigrun R.. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Winkler, Stefan. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Pessler, Frank. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania. Helmholtz Centre for Infection Research; Alemania
Fil: Kallinich, Tilmann. Universität zu Berlin; Alemania
Fil: Ganser, Gerd. Sendenhorst. St. Josef-Stift; Alemania
Fil: Nimtz-Talaska, Antje. Kinderrheumatologie; Alemania
Fil: Baumann, Ulrich. Hannover Medical School; Alemania
Fil: Runde, Volker. Wilhelm-Anton-Hospital; Alemania
Fil: Grimbacher, Bodo. University Hospital Freiburg; Alemania
Fil: Birmelin, Jennifer. University Hospital Freiburg; Alemania
Fil: Gahr, Manfred. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Roesler, Joachim. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
Fil: Rösen-Wolff, Angela. University Hospital Carl Gustav Carus. Department of Pediatrics. Dresden; Alemania
description Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. In- flammation is often mediated by enzymatic activation of interleukin (IL)-1β and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1β releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation.
publishDate 2013
dc.date.none.fl_str_mv 2013-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/24124
Luksch, Hella; Romanowski, Michael J.; Chara, Osvaldo; Tuengler, Victoria; Caffarena, Ernesto Raúl; et al.; Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β; Wiley-liss, Div John Wiley & Sons Inc; Human Mutation; 34; 1; 1-2013; 122-131
1059-7794
CONICET Digital
CONICET
url http://hdl.handle.net/11336/24124
identifier_str_mv Luksch, Hella; Romanowski, Michael J.; Chara, Osvaldo; Tuengler, Victoria; Caffarena, Ernesto Raúl; et al.; Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1β; Wiley-liss, Div John Wiley & Sons Inc; Human Mutation; 34; 1; 1-2013; 122-131
1059-7794
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/humu.22169/abstract
info:eu-repo/semantics/altIdentifier/doi/10.1002/humu.22169
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley-liss, Div John Wiley & Sons Inc
publisher.none.fl_str_mv Wiley-liss, Div John Wiley & Sons Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846782174873780224
score 12.982451

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