MRC National Institute for Medical Research, London
Science for Health
T cell antigen receptor–induced proliferation
08 December 2008
NF-κB transcription factors play a critical role in the regulation of cellular genes involved in immune and inflammatory responses. Mammals express five NF-κB proteins: Rel-A, Rel-B, c-Rel, NF-κB1 p50 and NF-κB2 p52. These bind to DNA as homo- or heterodimers and are primarily regulated by inhibitory proteins, the IκBs, which bind and retain them in the cytoplasm of unstimulated cells. In response to stimulation with agonists, IκBs are phosphorylated and then degraded by the proteasome, releasing associated NF-κB dimers to translocate into the nucleus and modulate specific gene transcription.
The 105 kDa precursor form of NF-κB1 (p105) functions as an IκB and is degraded by the proteasome after phosphorylation by the IκB kinase complex to release associated NF-κB dimers. However, the physiological role of the ‘p105 signalling pathway’ in NF-κB activation has remained unclear.
Steve Ley (pictured) and his coworkers, in NIMR's Division of Immune Cell Biology, have generated a novel knock-in mouse strain in which stimulus-induced proteolysis of p105 is blocked. Analysis of these mutant mice has demonstrated that p105 proteolysis plays a critical role in optimal T cell antigen receptor-induced activation of NF-κB and mature CD4
Our work shows that the p105 pathway is not required for normal development, but is critical for optimal T cell activation in adaptive immune responses. This contrasts with the canonical and alternative NF-κB pathways that are essential for liver development and secondary lymphoid organ development, respectively. The more restricted role of the p105 pathway for inducible gene expression in immune responses suggests that it might be a suitable target for drugs designed to treat autoimmune diseases. We are planning to address this possibility in future studies by testing our p105 knock-in mice in a model for inflammatory bowel disease
Steve Ley
Original article
The research findings are published in full in:
Srividya Sriskantharajah, Monica P Belich, Stamatia Papoutsopoulou, Julia Janzen, Victor Tybulewicz, Benedict Seddon & Steven C Ley
Proteolysis of NF-κB1 p105 is essential for T cell antigen receptor–induced proliferation
Nature Immunology, epub ahead of print. Publisher abstract
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