Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype

  • J Clin Invest. 2022 Mar 15;132(6):e128808. doi: 10.1172/JCI128808.
Younglang Lee  1  2 ,  Alex W Wessel  1  2 ,  Jiazhi Xu  3 ,  Julia G Reinke  3 ,  Eries Lee  1  2 ,  Somin M Kim  1  2 ,  Amy P Hsu  4 ,  Jevgenia Zilberman-Rudenko  1  2 ,  Sha Cao  5 ,  Clinton Enos  1  2 ,  Stephen R Brooks  6 ,  Zuoming Deng  6 ,  Bin Lin  7 ,  Adriana A de Jesus  7 ,  Daniel N Hupalo  8 ,  Daniela Gp Piotto  9 ,  Maria T Terreri  9 ,  Victoria R Dimitriades  10 ,  Clifton L Dalgard  8  11 ,  Steven M Holland  4 ,  Raphaela Goldbach-Mansky  7 ,  Richard M Siegel  2  12 ,  Eric P Hanson  3
Affiliations
  • 1. Immunodeficiency and Inflammatory Disease Unit and.
  • 2. Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA.
  • 3. Indiana University School of Medicine, Wells Center for Pediatric Research, Indianapolis, Indiana, USA.
  • 4. Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
  • 5. Department of Biostatistics, Indiana University, School of Medicine, Indianapolis, Indiana, USA.
  • 6. Biodata Mining and Discovery Section, Office of Science and Technology, NIAMS and.
  • 7. Translational Autoinflammatory Diseases Section (TADS), LCIM, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
  • 8. The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
  • 9. Escola Paulista de Medicina/Universidade Federal de São Paulo, São Paulo, Brazil.
  • 10. Division of Infectious Diseases, Immunology & Allergy University of California Davis Health, Sacramento, California, USA.
  • 11. Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
  • 12. Novartis Institutes for BioMedical Research WSJ, Basel, Switzerland.
PMID: 35289316 DOI: 10.1172/JCI128808
Abstract

Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I-like Receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and Antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.

Keywords
Genetic diseases; Genetics; Immunology; Inflammation; Innate immunity; Signal transduction.