PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development

• Ram K C Venigalla ^[3] ; Victoria A McGuire ^[3] ; Rosemary Clarke ^[1] ; Janet C Patterson-Kane ^[2] ; Ayaz Najafov ^[3] ; Rachel Toth ^[3] ; Pierre C McCarthy ^[3] ; Frederick Simeons ^[1] ; Laste Stojanovski ^[1] ; J Simon C Arthur ^[4]
  1. [1] University of Dundee

     University of Dundee

     Reino Unido

     
  2. [2] University of Glasgow

     University of Glasgow

     Reino Unido

     
  3. [3] MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, UK
  4. [4] MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, UK; Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee, Dundee, UK

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 32, Nº. 7, 2013, págs. 1008-1022
• Idioma: inglés
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• Resumen

  • Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells.