Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility
dc.contributor.author | Wirasinha, Rushika C. | |
dc.contributor.author | Davies, Ainsley | |
dc.contributor.author | Srivastava, Monika | |
dc.contributor.author | Sheridan, Julie M. | |
dc.contributor.author | Sng, Xavier Y. X. | |
dc.contributor.author | Delmonte, Ottavia M. | |
dc.contributor.author | Dobbs, Kerry | |
dc.contributor.author | Loh, Khai L. | |
dc.contributor.author | Miosge, Lisa | |
dc.contributor.author | Lee, Cindy | |
dc.contributor.author | Chand, Rochna | |
dc.contributor.author | Chan, Anna | |
dc.contributor.author | Yap, Jin Yan | |
dc.contributor.author | Keller, Michael D. | |
dc.contributor.author | Chen, Karin | |
dc.contributor.author | Rossjohn, J. | |
dc.contributor.author | La Gruta, Nicole L. | |
dc.contributor.author | Vinuesa, Carola | |
dc.contributor.author | Reid, Hugh H. | |
dc.contributor.author | Lionakis, Michail S. | |
dc.contributor.author | Notarangelo, Luigi D. | |
dc.contributor.author | Gray, Daniel H. D. | |
dc.contributor.author | Goodnow, Christopher C. | |
dc.contributor.author | Cook, Matthew | |
dc.contributor.author | Daley, Stephen | |
dc.date.accessioned | 2021-02-11T01:32:16Z | |
dc.date.available | 2021-02-11T01:32:16Z | |
dc.date.issued | 2020-10-27 | |
dc.date.updated | 2021-12-02T05:03:29Z | |
dc.description.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. | |
dc.description.sponsorship | This work was funded by National Health and Medical Research Council grants 1107464 (M.C. Cook and S.R. Daley), 1108800 (C.C. Goodnow and S.R. Daley), 1079648 (C.G. Vinuesa and M.C. Cook), 1113577 (C.G. Vinuesa and M.C. Cook), 1145888 (D.H.D. Gray), 1158024 (D.H.D. Gray), and 1121325 (D.H.D. Gray); the Monash Biomedicine Discovery Institute; and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. | en_AU |
dc.format.mimetype | application/pdf | en_AU |
dc.identifier.issn | 0022-1007 | en_AU |
dc.identifier.uri | http://hdl.handle.net/1885/222464 | |
dc.language.iso | en_AU | en_AU |
dc.provenance | This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/) | en_AU |
dc.publisher | Rockefeller University Press | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1107464 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1108800 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1079648 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1113577 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1145888 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1121325 | |
dc.rights | © 2020 Wirasinha et al. | |
dc.rights.license | Attribution–Noncommercial–Share Alike–No Mirror Sites license | en_AU |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-sa/4.0/ | en_AU |
dc.source | Journal of Experimental Medicine | |
dc.title | Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility | |
dc.type | Journal article | |
dcterms.accessRights | Open Access | en_AU |
dcterms.dateAccepted | 2020-08-21 | |
local.bibliographicCitation.issue | 2 | en_AU |
local.bibliographicCitation.lastpage | 19 | en_AU |
local.bibliographicCitation.startpage | 1 | en_AU |
local.contributor.affiliation | Wirasinha, Rushika C., Monash University | en_AU |
local.contributor.affiliation | Davies, Ainsley, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Srivastava, Monika, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Sheridan, Julie M., Walter and Eliza Hall Institute of Medical Research | en_AU |
local.contributor.affiliation | Sng, Xavier Y. X., Monash University | en_AU |
local.contributor.affiliation | Delmonte, Ottavia M., National Institute of Health | en_AU |
local.contributor.affiliation | Dobbs, Kerry, National Institute of Health | en_AU |
local.contributor.affiliation | Loh, Khai L., Monash University | en_AU |
local.contributor.affiliation | Miosge, Lisa, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Lee, Cindy, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Chand, Rochna, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Chan, Anna, Monash University | en_AU |
local.contributor.affiliation | Yap, Jin Yan, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Keller, Michael D., Children's National Medical Centre | en_AU |
local.contributor.affiliation | Chen, Karin, University of Utah | en_AU |
local.contributor.affiliation | Rossjohn, J., Monash University | en_AU |
local.contributor.affiliation | La Gruta, Nicole L., Monash University | en_AU |
local.contributor.affiliation | Garcia De Vinuesa, Maria Carola, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Reid, Hugh H., Monash University | en_AU |
local.contributor.affiliation | Lionakis, Michail S., National Institute of Health | en_AU |
local.contributor.affiliation | Notarangelo, Luigi D., National Institute of Health | en_AU |
local.contributor.affiliation | Gray, Daniel H.D., The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia | en_AU |
local.contributor.affiliation | Goodnow, Christopher C., Garvan Institute of Medical Research | en_AU |
local.contributor.affiliation | Cook, Matthew, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Daley, Stephen, Monash University | en_AU |
local.contributor.authoremail | u4164556@anu.edu.au | en_AU |
local.contributor.authoruid | Davies, Ainsley, u5371176 | en_AU |
local.contributor.authoruid | Srivastava, Monika, u4355780 | en_AU |
local.contributor.authoruid | Miosge, Lisa, u9817053 | en_AU |
local.contributor.authoruid | Lee, Cindy, u4973537 | en_AU |
local.contributor.authoruid | Chand, Rochna, u5165699 | en_AU |
local.contributor.authoruid | Yap, Jin Yan, u4729669 | en_AU |
local.contributor.authoruid | Garcia De Vinuesa, Maria Carola, u4164556 | en_AU |
local.contributor.authoruid | Cook, Matthew, u2572788 | en_AU |
local.description.notes | Imported from ARIES | en_AU |
local.identifier.absfor | 110704 - Cellular Immunology | en_AU |
local.identifier.absfor | 110706 - Immunogenetics (incl. Genetic Immunology) | en_AU |
local.identifier.absseo | 920110 - Inherited Diseases (incl. Gene Therapy) | en_AU |
local.identifier.absseo | 920108 - Immune System and Allergy | en_AU |
local.identifier.ariespublication | u1080391xPUB13 | en_AU |
local.identifier.citationvolume | 218 | en_AU |
local.identifier.doi | 10.1084/jem.20200476 | en_AU |
local.identifier.scopusID | 2-s2.0-85094932574 | |
local.identifier.uidSubmittedBy | u1080391 | en_AU |
local.publisher.url | https://rupress.org/ | en_AU |
local.type.status | Published Version | en_AU |
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