2026-06-14T05:04:48Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/74092025-05-30T16:12:47Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609
Repisalud
author
Coiras, Mayte
author
Lopez-Huertas, Maria Rosa
author
Mateos, Elena
author
Alcamí, José
funder
Instituto de Salud Carlos III
funder
Fundación para la Innovación y la Prospectiva en Salud en España
funder
Comunidad de Madrid (España)
2019-03-27T12:47:22Z
2019-03-27T12:47:22Z
2008-12-01
Retrovirology. 2008 Dec 1;5:109.
10.1186/1742-4690-5-109
1742-4690
Retrovirology
19046417
http://hdl.handle.net/20.500.12105/7409
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.
eng
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
research article
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Caspase3MediatedCcleavage_2008.pdf
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Caspase3MediatedCcleavage_2008.pdf.txt