Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes

BACKGROUND: Degradation of p65/RelA has been involved in both the inhibition of NF-kappaB-dependent activity and the onset of apoptosis. However, the mechanisms of NF-kappaB degradation are unclear and can vary depending on the cell type. Cleavage of p65/RelA can produce an amino-terminal fragment t...

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Autores: Coiras, Mayte, Lopez-Huertas, Maria Rosa, Mateos, Elena, Alcamí, José
Formato: artículo
Fecha de publicación:2008
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7409
Acesso em linha:http://hdl.handle.net/20.500.12105/7409
Access Level:acceso abierto
Palavra-chave:Caspase 3
Cells, Cultured
Dimerization
HIV-1
Humans
I-kappa B Proteins
NF-KappaB Inhibitor alpha
Protein Binding
T-Lymphocytes
Transcription Factor RelA
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spelling Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytesCoiras, MayteLopez-Huertas, Maria RosaMateos, ElenaAlcamí, JoséCaspase 3Cells, CulturedDimerizationHIV-1HumansI-kappa B ProteinsNF-KappaB Inhibitor alphaProtein BindingT-LymphocytesTranscription Factor RelABACKGROUND: Degradation of p65/RelA has been involved in both the inhibition of NF-kappaB-dependent activity and the onset of apoptosis. However, the mechanisms of NF-kappaB degradation are unclear and can vary depending on the cell type. Cleavage of p65/RelA can produce an amino-terminal fragment that was shown to act as a dominant-negative inhibitor of NF-kappaB, thereby promoting apoptosis. However, the opposite situation has also been described and the production of a carboxy-terminal fragment that contains two potent transactivation domains has also been related to the onset of apoptosis. In this context, a carboxy-terminal fragment of p65/RelA (DeltaNH2p65), detected in non-apoptotic human T lymphocytes upon activation, has been studied. T cells constitute one of the long-lived cellular reservoirs of the human immunodeficiency virus type 1 (HIV-1). Because NF-kappaB is the most important inducible element involved in initiation of HIV-1 transcription, an adequate control of NF-kappaB response is of paramount importance for both T cell survival and viral spread. Its major inhibitor IkappaBalpha constitutes a master terminator of NF-kappaB response that is complemented by degradation of p65/RelA. RESULTS AND CONCLUSIONS: In this study, the function of a caspase-3-mediated carboxy-terminal fragment of p65/RelA, which was detected in activated human peripheral blood lymphocytes (PBLs), was analyzed. Cells producing this truncated p65/RelA did not undergo apoptosis but showed a high viability, in spite of caspase-3 activation. DeltaNH2p65 lacked most of DNA-binding domain but retained the dimerization domain, NLS and transactivation domains. Consequently, it could translocate to the nucleus, associate with NF-kappaB1/p50 and IkappaBalpha, but could not bind -kappaB consensus sites. However, although DeltaNH2p65 lacked transcriptional activity by itself, it could increase NF-kappaB activity in a dose-dependent manner by hijacking IkappaBalpha. Thus, its expression resulted in a persistent transactivation activity of wild-type p65/RelA, as well as an improvement of HIV-1 replication in PBLs. Moreover, DeltaNH2p65 was increased in the nuclei of PMA-, PHA-, and TNFalpha-activated T cells, proving this phenomenon was related to cell activation. These data suggest the existence of a novel mechanism for maintaining NF-kappaB activity in human T cells through the binding of the carboxy-terminal fragment of p65/RelA to IkappaBalpha in order to protect wild-type p65/RelA from IkappaBalpha inhibition.BioMed Central (BMC)Instituto de Salud Carlos IIIFundación para la Innovación y la Prospectiva en Salud en EspañaComunidad de Madrid (España)20192019-03-2720082008-12-0120082008-12-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/7409reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES RD06 0006ES PI040614 Not availableopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/74092026-06-12T12:43:37Z
dc.title.none.fl_str_mv Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes
title Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes
spellingShingle Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes
Coiras, Mayte
Caspase 3
Cells, Cultured
Dimerization
HIV-1
Humans
I-kappa B Proteins
NF-KappaB Inhibitor alpha
Protein Binding
T-Lymphocytes
Transcription Factor RelA
title_short Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes
title_full Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes
title_fullStr Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes
title_full_unstemmed Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes
title_sort Caspase-3-mediated cleavage of p65/RelA results in a carboxy-terminal fragment that inhibits IkappaBalpha and enhances HIV-1 replication in human T lymphocytes
dc.creator.none.fl_str_mv Coiras, Mayte
Lopez-Huertas, Maria Rosa
Mateos, Elena
Alcamí, José
author Coiras, Mayte
author_facet Coiras, Mayte
Lopez-Huertas, Maria Rosa
Mateos, Elena
Alcamí, José
author_role author
author2 Lopez-Huertas, Maria Rosa
Mateos, Elena
Alcamí, José
author2_role author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Fundación para la Innovación y la Prospectiva en Salud en España
Comunidad de Madrid (España)
dc.subject.none.fl_str_mv Caspase 3
Cells, Cultured
Dimerization
HIV-1
Humans
I-kappa B Proteins
NF-KappaB Inhibitor alpha
Protein Binding
T-Lymphocytes
Transcription Factor RelA
topic Caspase 3
Cells, Cultured
Dimerization
HIV-1
Humans
I-kappa B Proteins
NF-KappaB Inhibitor alpha
Protein Binding
T-Lymphocytes
Transcription Factor RelA
description BACKGROUND: Degradation of p65/RelA has been involved in both the inhibition of NF-kappaB-dependent activity and the onset of apoptosis. However, the mechanisms of NF-kappaB degradation are unclear and can vary depending on the cell type. Cleavage of p65/RelA can produce an amino-terminal fragment that was shown to act as a dominant-negative inhibitor of NF-kappaB, thereby promoting apoptosis. However, the opposite situation has also been described and the production of a carboxy-terminal fragment that contains two potent transactivation domains has also been related to the onset of apoptosis. In this context, a carboxy-terminal fragment of p65/RelA (DeltaNH2p65), detected in non-apoptotic human T lymphocytes upon activation, has been studied. T cells constitute one of the long-lived cellular reservoirs of the human immunodeficiency virus type 1 (HIV-1). Because NF-kappaB is the most important inducible element involved in initiation of HIV-1 transcription, an adequate control of NF-kappaB response is of paramount importance for both T cell survival and viral spread. Its major inhibitor IkappaBalpha constitutes a master terminator of NF-kappaB response that is complemented by degradation of p65/RelA. RESULTS AND CONCLUSIONS: In this study, the function of a caspase-3-mediated carboxy-terminal fragment of p65/RelA, which was detected in activated human peripheral blood lymphocytes (PBLs), was analyzed. Cells producing this truncated p65/RelA did not undergo apoptosis but showed a high viability, in spite of caspase-3 activation. DeltaNH2p65 lacked most of DNA-binding domain but retained the dimerization domain, NLS and transactivation domains. Consequently, it could translocate to the nucleus, associate with NF-kappaB1/p50 and IkappaBalpha, but could not bind -kappaB consensus sites. However, although DeltaNH2p65 lacked transcriptional activity by itself, it could increase NF-kappaB activity in a dose-dependent manner by hijacking IkappaBalpha. Thus, its expression resulted in a persistent transactivation activity of wild-type p65/RelA, as well as an improvement of HIV-1 replication in PBLs. Moreover, DeltaNH2p65 was increased in the nuclei of PMA-, PHA-, and TNFalpha-activated T cells, proving this phenomenon was related to cell activation. These data suggest the existence of a novel mechanism for maintaining NF-kappaB activity in human T cells through the binding of the carboxy-terminal fragment of p65/RelA to IkappaBalpha in order to protect wild-type p65/RelA from IkappaBalpha inhibition.
publishDate 2008
dc.date.none.fl_str_mv 2008
2008-12-01
2008
2008-12-01
2019
2019-03-27
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/7409
url http://hdl.handle.net/20.500.12105/7409
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES RD06 0006
ES PI040614 Not available
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BioMed Central (BMC)
publisher.none.fl_str_mv BioMed Central (BMC)
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812455

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