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Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility

Wirasinha, Rushika C., Davies, Ainsley R., Srivastava, Monika, Sheridan, Julie M., Sng, Xavier Y.X., Delmonte, Ottavia M., Dobbs, Kerry, Loh, Khai L., Miosge, Lisa A., Lee, Cindy Eunhee, Chand, Rochna, Chan, Anna, Yap, Jin Yan, Keller, Michael D., Chen, Karin, Rossjohn, Jamie, La Gruta, Nicole L., Vinuesa, Carola G., Reid, Hugh H., Lionakis, Michail S., Notarangelo, Luigi D., Gray, Daniel H.D., Goodnow, Christopher C., Cook, Matthew C. and Daley, Stephen R. 2021. Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility. Journal of Experimental Medicine 218 (2) , e20200476. 10.1084/jem.20200476

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Abstract

NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that is partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IκB function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Rockefeller University Press
ISSN: 0022-1007
Date of First Compliant Deposit: 4 February 2021
Date of Acceptance: 21 August 2020
Last Modified: 04 Feb 2021 14:30
URI: https://orca.cardiff.ac.uk/id/eprint/138204

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