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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/24124
Ver los metadatos del registro completo
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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 Técnicas2025-09-29T10:16:54Zoai: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:34982025-09-29 10:16:54.37CONICET 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 |
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1844614117421219840 |
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13.070432 |