학술논문
Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype
Document Type
article
Author
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
Source
Journal of Clinical Investigation. 132(6)
Subject
Language
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.