Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype

• Published in: The Journal of clinical investigation 2022-03, Vol.132 (6), p.1-16
• Main Authors: Lee, Younglang, Wessel, Alex W, Xu, Jiazhi, Reinke, Julia G, Lee, Eries, Kim, Somin M, Hsu, Amy P, Zilberman-Rudenko, Jevgenia, Cao, Sha, Enos, Clinton, Brooks, Stephen R, Deng, Zuoming, Lin, Bin, de Jesus, Adriana A, Hupalo, Daniel N, Piotto, Daniela GP, Terreri, Maria T, Dimitriades, Victoria R, Dalgard, Clifton L, Holland, Steven M, Goldbach-Mansky, Raphaela, Siegel, Richard M, Hanson, Eric P
• Format: Article
• Language: English
• Subjects: Alternative splicing; Biomedical research; Blood cells; Enzyme inhibitors; Fibroblasts; Genotype & phenotype; IKK protein; Immune system; Immunodeficiency; Inflammation; Inflammatory diseases; Interferon; Kinases; Lymphocytes; Lymphocytes T; Macrophages; Monocytes; Mutation; NF-κB protein; Patients; Pediatrics; Phenotypes; Proteins; TLR3 protein; Toll-like receptors; Transcription; Transcription factors; Tumor necrosis factor; Viral infections
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI128808.

Host defense and inflammation are regulated by the NF-kB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-kB 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- \ex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-kB 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-Aex5 exhibited increased NF-kB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-kB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Aex5, 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-offunction IKBKG mutations.