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...
| Autores: | , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2008 |
| País: | España |
| Institución: | Instituto de Salud Carlos III (ISCIII) |
| Repositorio: | Repisalud |
| Idioma: | inglés |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/7409 |
| Acceso en línea: | http://hdl.handle.net/20.500.12105/7409 |
| Access Level: | acceso abierto |
| Palabra clave: | Caspase 3 Cells, Cultured Dimerization HIV-1 Humans I-kappa B Proteins NF-KappaB Inhibitor alpha Protein Binding T-Lymphocytes Transcription Factor RelA |
| Sumario: | 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. |
|---|