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.
Sasaki
Yoshiteru
Y
Immune Disease Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. yoshisasaki@cdb.riken.jp
Calado
Dinis P
DP
Derudder
Emmanuel
E
Zhang
Baochun
B
Shimizu
Yuri
Y
Mackay
Fabienne
F
Nishikawa
Shin-ichi
S
Rajewsky
Klaus
K
Schmidt-Supprian
Marc
M
D000818:Animals; D053264:B-Cell Activating Factor / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000276:immunology*; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse