Journal article

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

Rushika C Wirasinha, Ainsley R Davies, Monika Srivastava, Julie M Sheridan, Xavier YX Sng, Ottavia M Delmonte, Kerry Dobbs, Khai L Loh, Lisa A Miosge, Cindy Eunhee Lee, Rochna Chand, Anna Chan, Jin Yan Yap, Michael D Keller, Karin Chen, Jamie Rossjohn, Nicole L La Gruta, Carola G Vinuesa, Hugh H Reid, Michail S Lionakis Show all

JOURNAL OF EXPERIMENTAL MEDICINE | ROCKEFELLER UNIV PRESS | Published : 2021

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..

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Grants

Awarded by National Health and Medical Research Council


Funding Acknowledgements

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); theMonash Biomedicine Discovery Institute; and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. This study utilized the Australian Phenomics Network Histopathology and Organ Pathology Service of the University of Melbourne.