NIK overexpression amplifies, whereas ablation of its TRAF3-binding domain replaces BAFF:BAFF-R-mediated survival signals in B cells
BAFF-R-dependent activation of the alternative NF-kappaB pathway plays an essential role in mature B cell survival. Mutations leading to overexpression of NIK and deletion of the TRAF3 gene are implicated in human multiple myeloma. We show that overexpression of NIK in mouse B lymphocytes amplifies alternative NF-kappaB activation and peripheral B cell numbers in a BAFF-R-dependent manner, whereas uncoupling NIK from TRAF3-mediated control causes maximal p100 processing and dramatic hyperplasia of BAFF-R-independent B cells. NIK controls alternative NF-kappaB signaling by increasing the protein levels of its negative regulator TRAF3 in a dose-dependent fashion. This mechanism keeps NIK protein levels below detection even when they cause B cell hyperplasia, so that contributions of NIK to B cell pathologies can easily be overlooked.
|Authors||Sasaki, Y. Calado, D. P. Derudder, E. Zhang, B. Shimizu, Y. Mackay, F. Nishikawa, S. Rajewsky, K. Schmidt-Supprian, M.|
|Published Date||2008-08-05 00:00:00|
|OpenAccess Link||https://publications.gimr.garvan.org.au/download.php?10144_10255/08 Sasaki PNASb10883-8.pdf|