Analysis of the domain specific functions of IKK1 and the role of the alternative NFkappaB pathway and IKK1 in germinal center B cells

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The transcription factor NFkappaB plays a central role in the inducible expression of many genes involved in the mechanisms of innate and adaptive immunity. The two dominant signaling pathways which can lead to the activation of NFkappaB are called the classical and the alternative pathway. The alternative NFkappaB pathway is characterised by the IKK1 mediated phosphorylation of p100 which leads to the release of the NFkappaB dimer p52/RelB. IKK1 itself is activated by NIK mediated phosphorylation. Very recently it was shown in the group of Prof.Dr.Rickert that B cells expressing a mutant IKK1 molecule that cannot be phosphorylated by NIK (IKKAA) do not form germinal centers. The goal of the proposed project is to study the mechanism leading to this phenotype. The main objectives are to analyse the NIK-dependent signaling in B cells, determine the biochemical defects in IKKAA B cells, analyze the intrinsic functions of IKK1 in antigen presenting- and plasma- cells. Further, recent studies indicate that IKK1 possesses also NIK- independent, kinase independent or nuclear functions. To gain insight into these aspects of IKK1 function, B cells expressing IKK1 molecules that a) are unable to enter he nucleus (IKK1NLS) b)are kinase inactive (IKK1KM) c)are constitutively active (IKK1EE) will be studied.