Proteolysis of NF-kB1 p105 is vital for its function as a precursor to p50 and as an IkB. This occurs in two ways, both mediated by the proteasome. A constitutive proteolytic removal of the p105 C-terminus, termed processing, generates the mature transcription factor p50. In contrast, a signal-induced p105 proteolysis is triggered by phosphorylation of serines 927 and 932 in the p105 PEST region by the IKK complex. This promotes p105 poly-ubiquitination and subsequent complete degradation. IKK-induced p105 proteolysis has been demonstrated to regulate the kinase activity of the MAP3K TPL-2, since all detectable TPL-2 is found in a complex with p105. Furthermore, NF-kB1 p105 retains Rel subunits in the cytoplasm via interaction with the p105 C-terminal ankyrin repeat region. However, it is unclear whether IKK-induced p105 proteolysis contributes to NF-kB activation, though this process would be expected to release Rel subunits to translocate into the nucleus. A large body of evidence exists to suggest a major role for NF-kB in T cell development and function. To investigate the significance of IKK-induced p105 degradation in T cells, a knock-in mouse strain, Nfkb1S927A'S93ZA, in which serines 927 and 932 of NF-kB1 p105 were mutated to alanine residues was analysed. Previous work has shown that constitutive processing of pio5S927A S932A to p50 occurs normally, but this mutated p105 is refractory to IKK-induced proteolysis. Work presented here demonstrates that whilst p105 mutation did not affect thymic differentiation of CD4+ and CD8+ T cells, numbers of CD4+CD25+ regulatory T cells, memory-phenotype CD4+ T cells and thymic NKT cells were significantly reduced. Analysis of BM chimeras revealed cell autonomous and non-haematopoietic defects required for generation of these sub-populations. In vitro experiments indicated that TCR-induced proliferation was significantly impaired in /Vflcb7S927A S932A CD4+ T cells, due partly to reduced interleukin-2 production. In contrast, p105 mutation had no effect on CD4+ T cell survival. These defects were not due to a lack of TPL-2 activity, based on analysis of TPL-2-deficient mice. This study presents evidence to suggest a critical role for IKK-induced p105 proteolysis in regulating NF-kB activation in T lymphocytes.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:498561 |
| Date | January 2008 |
| Creators | Sriskantharajah, Srividya |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1446121/ |
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