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

Simple item page
dc.contributor.authorWirasinha, Rushika C.
dc.contributor.authorDavies, Ainsley
dc.contributor.authorSrivastava, Monika
dc.contributor.authorSheridan, Julie M.
dc.contributor.authorSng, Xavier Y. X.
dc.contributor.authorDelmonte, Ottavia M.
dc.contributor.authorDobbs, Kerry
dc.contributor.authorLoh, Khai L.
dc.contributor.authorMiosge, Lisa
dc.contributor.authorLee, Cindy
dc.contributor.authorChand, Rochna
dc.contributor.authorChan, Anna
dc.contributor.authorYap, Jin Yan
dc.contributor.authorKeller, Michael D.
dc.contributor.authorChen, Karin
dc.contributor.authorRossjohn, J.
dc.contributor.authorLa Gruta, Nicole L.
dc.contributor.authorVinuesa, Carola
dc.contributor.authorReid, Hugh H.
dc.contributor.authorLionakis, Michail S.
dc.contributor.authorNotarangelo, Luigi D.
dc.contributor.authorGray, Daniel H. D.
dc.contributor.authorGoodnow, Christopher C.
dc.contributor.authorCook, Matthew
dc.contributor.authorDaley, Stephen
dc.date.accessioned2021-02-11T01:32:16Z
dc.date.available2021-02-11T01:32:16Z
dc.date.issued2020-10-27
dc.date.updated2021-12-02T05:03:29Z
dc.description.abstractNF-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.sponsorshipThis 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.mimetypeapplication/pdfen_AU
dc.identifier.issn0022-1007en_AU
dc.identifier.urihttp://hdl.handle.net/1885/222464
dc.language.isoen_AUen_AU
dc.provenanceThis 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.publisherRockefeller University Press
dc.relationhttp://purl.org/au-research/grants/nhmrc/1107464
dc.relationhttp://purl.org/au-research/grants/nhmrc/1108800
dc.relationhttp://purl.org/au-research/grants/nhmrc/1079648
dc.relationhttp://purl.org/au-research/grants/nhmrc/1113577
dc.relationhttp://purl.org/au-research/grants/nhmrc/1145888
dc.relationhttp://purl.org/au-research/grants/nhmrc/1121325
dc.rights© 2020 Wirasinha et al.
dc.rights.licenseAttribution–Noncommercial–Share Alike–No Mirror Sites licenseen_AU
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0/en_AU
dc.sourceJournal of Experimental Medicine
dc.titleNfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility
dc.typeJournal article
dcterms.accessRightsOpen Accessen_AU
dcterms.dateAccepted2020-08-21
local.bibliographicCitation.issue2en_AU
local.bibliographicCitation.lastpage19en_AU
local.bibliographicCitation.startpage1en_AU
local.contributor.affiliationWirasinha, Rushika C., Monash Universityen_AU
local.contributor.affiliationDavies, Ainsley, College of Health and Medicine, ANUen_AU
local.contributor.affiliationSrivastava, Monika, College of Health and Medicine, ANUen_AU
local.contributor.affiliationSheridan, Julie M., Walter and Eliza Hall Institute of Medical Researchen_AU
local.contributor.affiliationSng, Xavier Y. X., Monash Universityen_AU
local.contributor.affiliationDelmonte, Ottavia M., National Institute of Healthen_AU
local.contributor.affiliationDobbs, Kerry, National Institute of Healthen_AU
local.contributor.affiliationLoh, Khai L., Monash Universityen_AU
local.contributor.affiliationMiosge, Lisa, College of Health and Medicine, ANUen_AU
local.contributor.affiliationLee, Cindy, College of Health and Medicine, ANUen_AU
local.contributor.affiliationChand, Rochna, College of Health and Medicine, ANUen_AU
local.contributor.affiliationChan, Anna, Monash Universityen_AU
local.contributor.affiliationYap, Jin Yan, College of Health and Medicine, ANUen_AU
local.contributor.affiliationKeller, Michael D., Children's National Medical Centreen_AU
local.contributor.affiliationChen, Karin, University of Utahen_AU
local.contributor.affiliationRossjohn, J., Monash Universityen_AU
local.contributor.affiliationLa Gruta, Nicole L., Monash Universityen_AU
local.contributor.affiliationGarcia De Vinuesa, Maria Carola, College of Health and Medicine, ANUen_AU
local.contributor.affiliationReid, Hugh H., Monash Universityen_AU
local.contributor.affiliationLionakis, Michail S., National Institute of Healthen_AU
local.contributor.affiliationNotarangelo, Luigi D., National Institute of Healthen_AU
local.contributor.affiliationGray, Daniel H.D., The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australiaen_AU
local.contributor.affiliationGoodnow, Christopher C., Garvan Institute of Medical Researchen_AU
local.contributor.affiliationCook, Matthew, College of Health and Medicine, ANUen_AU
local.contributor.affiliationDaley, Stephen, Monash Universityen_AU
local.contributor.authoremailu4164556@anu.edu.auen_AU
local.contributor.authoruidDavies, Ainsley, u5371176en_AU
local.contributor.authoruidSrivastava, Monika, u4355780en_AU
local.contributor.authoruidMiosge, Lisa, u9817053en_AU
local.contributor.authoruidLee, Cindy, u4973537en_AU
local.contributor.authoruidChand, Rochna, u5165699en_AU
local.contributor.authoruidYap, Jin Yan, u4729669en_AU
local.contributor.authoruidGarcia De Vinuesa, Maria Carola, u4164556en_AU
local.contributor.authoruidCook, Matthew, u2572788en_AU
local.description.notesImported from ARIESen_AU
local.identifier.absfor110704 - Cellular Immunologyen_AU
local.identifier.absfor110706 - Immunogenetics (incl. Genetic Immunology)en_AU
local.identifier.absseo920110 - Inherited Diseases (incl. Gene Therapy)en_AU
local.identifier.absseo920108 - Immune System and Allergyen_AU
local.identifier.ariespublicationu1080391xPUB13en_AU
local.identifier.citationvolume218en_AU
local.identifier.doi10.1084/jem.20200476en_AU
local.identifier.scopusID2-s2.0-85094932574
local.identifier.uidSubmittedByu1080391en_AU
local.publisher.urlhttps://rupress.org/en_AU
local.type.statusPublished Versionen_AU

Downloads

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
01_Wirasinha_Nfkb2_variants_reveal_a_2020.pdf
Size:
7.48 MB
Format:
Adobe Portable Document Format
Download

Collections

ANU Research Publications

DSpace software copyright © 2002-2024 LYRASIS