Modelling phagosomal lipid networks that regulate actin assembly

Autores
Kühnel, Marck; Mayorga, Luis Segundo; Dandekar, Thomas; Thakar, Juilee; Schwarz, Roland; Anes, Elsa; Griffiths, Gareth; Reich, Jens
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: When purified phagosomes are incubated in the presence of actin under appropriate conditions, microfilaments start growing from the membrane in a process that is affected by ATP and the lipid composition of the membrane. Isolated phagosomes are metabolically active organelles that contain enzymes and metabolites necessary for lipid interconversion. Hence, addition of ATP, lipids, and actin to the system alter the steady-state composition of the phagosomal membrane at the same time that the actin nucleation is initiated. Our aim was to model all these processes in parallel. Results: We compiled detailed experimental data on the effects of different lipids and ATP on actin nucleation and we investigated experimentally lipid interconversion and ATP metabolism in phagosomes by using suitable radioactive compounds. In a first step, a complex lipid network interconnected by chemical reactions catalyzed by known enzymes was modelled in COPASI (Complex Pathway Simulator). However, several lines of experimental evidence indicated that only the phosphatidylinositol branch of the network was active, an observation that dramatically reduced the number of parameters in the model. The results also indicated that a lipid network-independent ATP-consuming activity should be included in the model. When this activity was introduced, the set of differential equations satisfactorily reproduced the experimental data. On the other hand, a molecular mechanism connecting membrane lipids, ATP, and the actin nucleation process is still missing. We therefore adopted a phenomenological (black-box) approach to represent the empirical observations. We proposed that lipids and ATP influence the dynamic interconversion between active and inactive actin nucleation sites. With this simple model, all the experimental data were satisfactorily fitted with a single positive parameter per lipid and ATP. Conclusion: By establishing an active 'dialogue' between an initial complex model and experimental observations, we could narrow the set of differential equations and parameters required to characterize the time-dependent changes of metabolites influencing actin nucleation on phagosomes. For this, the global model was dissected into three sub-models: ATP consumption, lipid interconversion, and nucleation of actin on phagosomal membranes. This scheme allowed us to describe this complex system with a relatively small set of differential equations and kinetic parameters that satisfactorily reproduced the experimental data.
Fil: Kühnel, Marck. European Molecular Biology Laboratory; Alemania
Fil: Mayorga, Luis Segundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. European Molecular Biology Laboratory; Alemania
Fil: Dandekar, Thomas. Universität Würzburg; Alemania
Fil: Thakar, Juilee. State University of Pennsylvania; Estados Unidos
Fil: Schwarz, Roland. Universität Würzburg; Alemania
Fil: Anes, Elsa. Universidad de Lisboa; Portugal
Fil: Griffiths, Gareth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. European Molecular Biology Laboratory; Alemania
Fil: Reich, Jens. Max-Delbrück-Centrum für Molekulare Medizin; Alemania
Materia
MATHEMATICAL MODEL
PHAGOSOME
MEMBRANE LIPIDS
PHOSPHOLIPIDS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/127528

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network_name_str CONICET Digital (CONICET)
spelling Modelling phagosomal lipid networks that regulate actin assemblyKühnel, MarckMayorga, Luis SegundoDandekar, ThomasThakar, JuileeSchwarz, RolandAnes, ElsaGriffiths, GarethReich, JensMATHEMATICAL MODELPHAGOSOMEMEMBRANE LIPIDSPHOSPHOLIPIDShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background: When purified phagosomes are incubated in the presence of actin under appropriate conditions, microfilaments start growing from the membrane in a process that is affected by ATP and the lipid composition of the membrane. Isolated phagosomes are metabolically active organelles that contain enzymes and metabolites necessary for lipid interconversion. Hence, addition of ATP, lipids, and actin to the system alter the steady-state composition of the phagosomal membrane at the same time that the actin nucleation is initiated. Our aim was to model all these processes in parallel. Results: We compiled detailed experimental data on the effects of different lipids and ATP on actin nucleation and we investigated experimentally lipid interconversion and ATP metabolism in phagosomes by using suitable radioactive compounds. In a first step, a complex lipid network interconnected by chemical reactions catalyzed by known enzymes was modelled in COPASI (Complex Pathway Simulator). However, several lines of experimental evidence indicated that only the phosphatidylinositol branch of the network was active, an observation that dramatically reduced the number of parameters in the model. The results also indicated that a lipid network-independent ATP-consuming activity should be included in the model. When this activity was introduced, the set of differential equations satisfactorily reproduced the experimental data. On the other hand, a molecular mechanism connecting membrane lipids, ATP, and the actin nucleation process is still missing. We therefore adopted a phenomenological (black-box) approach to represent the empirical observations. We proposed that lipids and ATP influence the dynamic interconversion between active and inactive actin nucleation sites. With this simple model, all the experimental data were satisfactorily fitted with a single positive parameter per lipid and ATP. Conclusion: By establishing an active 'dialogue' between an initial complex model and experimental observations, we could narrow the set of differential equations and parameters required to characterize the time-dependent changes of metabolites influencing actin nucleation on phagosomes. For this, the global model was dissected into three sub-models: ATP consumption, lipid interconversion, and nucleation of actin on phagosomal membranes. This scheme allowed us to describe this complex system with a relatively small set of differential equations and kinetic parameters that satisfactorily reproduced the experimental data.Fil: Kühnel, Marck. European Molecular Biology Laboratory; AlemaniaFil: Mayorga, Luis Segundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. European Molecular Biology Laboratory; AlemaniaFil: Dandekar, Thomas. Universität Würzburg; AlemaniaFil: Thakar, Juilee. State University of Pennsylvania; Estados UnidosFil: Schwarz, Roland. Universität Würzburg; AlemaniaFil: Anes, Elsa. Universidad de Lisboa; PortugalFil: Griffiths, Gareth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. European Molecular Biology Laboratory; AlemaniaFil: Reich, Jens. Max-Delbrück-Centrum für Molekulare Medizin; AlemaniaBioMed Central2008-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/127528Kühnel, Marck; Mayorga, Luis Segundo; Dandekar, Thomas; Thakar, Juilee; Schwarz, Roland; et al.; Modelling phagosomal lipid networks that regulate actin assembly; BioMed Central; Bmc Systems Biology; 2; 12-2008; 107-1081752-0509CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://bmcsystbiol.biomedcentral.com/articles/10.1186/1752-0509-2-107info:eu-repo/semantics/altIdentifier/doi/10.1186/1752-0509-2-107info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:30:12Zoai:ri.conicet.gov.ar:11336/127528instacron: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 10:30:12.69CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Modelling phagosomal lipid networks that regulate actin assembly
title Modelling phagosomal lipid networks that regulate actin assembly
spellingShingle Modelling phagosomal lipid networks that regulate actin assembly
Kühnel, Marck
MATHEMATICAL MODEL
PHAGOSOME
MEMBRANE LIPIDS
PHOSPHOLIPIDS
title_short Modelling phagosomal lipid networks that regulate actin assembly
title_full Modelling phagosomal lipid networks that regulate actin assembly
title_fullStr Modelling phagosomal lipid networks that regulate actin assembly
title_full_unstemmed Modelling phagosomal lipid networks that regulate actin assembly
title_sort Modelling phagosomal lipid networks that regulate actin assembly
dc.creator.none.fl_str_mv Kühnel, Marck
Mayorga, Luis Segundo
Dandekar, Thomas
Thakar, Juilee
Schwarz, Roland
Anes, Elsa
Griffiths, Gareth
Reich, Jens
author Kühnel, Marck
author_facet Kühnel, Marck
Mayorga, Luis Segundo
Dandekar, Thomas
Thakar, Juilee
Schwarz, Roland
Anes, Elsa
Griffiths, Gareth
Reich, Jens
author_role author
author2 Mayorga, Luis Segundo
Dandekar, Thomas
Thakar, Juilee
Schwarz, Roland
Anes, Elsa
Griffiths, Gareth
Reich, Jens
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MATHEMATICAL MODEL
PHAGOSOME
MEMBRANE LIPIDS
PHOSPHOLIPIDS
topic MATHEMATICAL MODEL
PHAGOSOME
MEMBRANE LIPIDS
PHOSPHOLIPIDS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Background: When purified phagosomes are incubated in the presence of actin under appropriate conditions, microfilaments start growing from the membrane in a process that is affected by ATP and the lipid composition of the membrane. Isolated phagosomes are metabolically active organelles that contain enzymes and metabolites necessary for lipid interconversion. Hence, addition of ATP, lipids, and actin to the system alter the steady-state composition of the phagosomal membrane at the same time that the actin nucleation is initiated. Our aim was to model all these processes in parallel. Results: We compiled detailed experimental data on the effects of different lipids and ATP on actin nucleation and we investigated experimentally lipid interconversion and ATP metabolism in phagosomes by using suitable radioactive compounds. In a first step, a complex lipid network interconnected by chemical reactions catalyzed by known enzymes was modelled in COPASI (Complex Pathway Simulator). However, several lines of experimental evidence indicated that only the phosphatidylinositol branch of the network was active, an observation that dramatically reduced the number of parameters in the model. The results also indicated that a lipid network-independent ATP-consuming activity should be included in the model. When this activity was introduced, the set of differential equations satisfactorily reproduced the experimental data. On the other hand, a molecular mechanism connecting membrane lipids, ATP, and the actin nucleation process is still missing. We therefore adopted a phenomenological (black-box) approach to represent the empirical observations. We proposed that lipids and ATP influence the dynamic interconversion between active and inactive actin nucleation sites. With this simple model, all the experimental data were satisfactorily fitted with a single positive parameter per lipid and ATP. Conclusion: By establishing an active 'dialogue' between an initial complex model and experimental observations, we could narrow the set of differential equations and parameters required to characterize the time-dependent changes of metabolites influencing actin nucleation on phagosomes. For this, the global model was dissected into three sub-models: ATP consumption, lipid interconversion, and nucleation of actin on phagosomal membranes. This scheme allowed us to describe this complex system with a relatively small set of differential equations and kinetic parameters that satisfactorily reproduced the experimental data.
Fil: Kühnel, Marck. European Molecular Biology Laboratory; Alemania
Fil: Mayorga, Luis Segundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. European Molecular Biology Laboratory; Alemania
Fil: Dandekar, Thomas. Universität Würzburg; Alemania
Fil: Thakar, Juilee. State University of Pennsylvania; Estados Unidos
Fil: Schwarz, Roland. Universität Würzburg; Alemania
Fil: Anes, Elsa. Universidad de Lisboa; Portugal
Fil: Griffiths, Gareth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. European Molecular Biology Laboratory; Alemania
Fil: Reich, Jens. Max-Delbrück-Centrum für Molekulare Medizin; Alemania
description Background: When purified phagosomes are incubated in the presence of actin under appropriate conditions, microfilaments start growing from the membrane in a process that is affected by ATP and the lipid composition of the membrane. Isolated phagosomes are metabolically active organelles that contain enzymes and metabolites necessary for lipid interconversion. Hence, addition of ATP, lipids, and actin to the system alter the steady-state composition of the phagosomal membrane at the same time that the actin nucleation is initiated. Our aim was to model all these processes in parallel. Results: We compiled detailed experimental data on the effects of different lipids and ATP on actin nucleation and we investigated experimentally lipid interconversion and ATP metabolism in phagosomes by using suitable radioactive compounds. In a first step, a complex lipid network interconnected by chemical reactions catalyzed by known enzymes was modelled in COPASI (Complex Pathway Simulator). However, several lines of experimental evidence indicated that only the phosphatidylinositol branch of the network was active, an observation that dramatically reduced the number of parameters in the model. The results also indicated that a lipid network-independent ATP-consuming activity should be included in the model. When this activity was introduced, the set of differential equations satisfactorily reproduced the experimental data. On the other hand, a molecular mechanism connecting membrane lipids, ATP, and the actin nucleation process is still missing. We therefore adopted a phenomenological (black-box) approach to represent the empirical observations. We proposed that lipids and ATP influence the dynamic interconversion between active and inactive actin nucleation sites. With this simple model, all the experimental data were satisfactorily fitted with a single positive parameter per lipid and ATP. Conclusion: By establishing an active 'dialogue' between an initial complex model and experimental observations, we could narrow the set of differential equations and parameters required to characterize the time-dependent changes of metabolites influencing actin nucleation on phagosomes. For this, the global model was dissected into three sub-models: ATP consumption, lipid interconversion, and nucleation of actin on phagosomal membranes. This scheme allowed us to describe this complex system with a relatively small set of differential equations and kinetic parameters that satisfactorily reproduced the experimental data.
publishDate 2008
dc.date.none.fl_str_mv 2008-12
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/11336/127528
Kühnel, Marck; Mayorga, Luis Segundo; Dandekar, Thomas; Thakar, Juilee; Schwarz, Roland; et al.; Modelling phagosomal lipid networks that regulate actin assembly; BioMed Central; Bmc Systems Biology; 2; 12-2008; 107-108
1752-0509
CONICET Digital
CONICET
url http://hdl.handle.net/11336/127528
identifier_str_mv Kühnel, Marck; Mayorga, Luis Segundo; Dandekar, Thomas; Thakar, Juilee; Schwarz, Roland; et al.; Modelling phagosomal lipid networks that regulate actin assembly; BioMed Central; Bmc Systems Biology; 2; 12-2008; 107-108
1752-0509
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1186/1752-0509-2-107
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
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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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