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A Novel Mutation in the Nfkb2 Gene Generates an NF-B2 "Super Repressor"¹

Elena Tucker^*,, Kristy O’Donnell, Martina Fuchsberger^*, Adrienne A. Hilton, Donald Metcalf, Kylie Greig, Natalie A. Sims^*,, Julian M. Quinn^*,, Warren S. Alexander^,, Douglas J. Hilton^,, Benjamin T. Kile^,, David M. Tarlinton^, and Robyn Starr^2,*,

^* St. Vincent’s Institute, Fitzroy, Victoria, Australia, The Walter and Eliza Hall Institute, and Department of Medicine, and Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

The noncanonical NF-B pathway regulates the development and function of multiple organs and cell lineages. We have generated mice harboring a novel mutation in Nfkb2 that prevents the processing of the inhibitory precursor, p100, into the active subunit, p52. Mutant mice express a complex phenotype with abnormalities in a variety of tissues, and with a spectrum that is more severe than in mice carrying a targeted deletion of Nfkb2. Signaling through the noncanonical pathway is ablated due to the absence of p52, resulting in disorganized splenic architecture and disrupted B cell development. The inhibitory precursor form of NF-B2 interacts with RelA, preventing activation of RelA dimers in response to both canonical and noncanonical stimuli, which in combination with p52 deficiency, results in defective lymph node formation and bone homeostasis. These findings demonstrate a key role for NF-B2 in the regulation of RelA activation and suggest overlap in the function of NF-B members in canonical and noncanonical pathway signaling.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Program Grant 257500 from the National Health and Medical Research Council. R.S. is supported by a Viertel Senior Medical Research Fellowship.

² Address correspondence and reprint requests to Dr. Robyn Starr, St. Vincent’s Institute, 41 Victoria Parade, Fitzroy Victoria 3065, Australia. E-mail address: rstarr{at}svi.edu.au

³ Abbreviations used in this paper: NIK, NF-B-inducing kinase; IKK, IB kinase; ENU, N-ethyl-N-nitrosourea; LT, lymphotoxin; LN, lymph node; RANKL, receptor activator of NF-B ligand; SP, single positive; wt, wild type.

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