UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-κB Signaling

• Published in: Diabetes (New York, N.Y.) Vol. 66; no. 7; pp. 2033 - 2043
• Main Authors: Ge, Yan, Paisie, Taylor K, Newman, Jeremy R B, McIntyre, Lauren M, Concannon, Patrick
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2017
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - immunology; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Enzyme-Linked Immunosorbent Assay; Gene Knockout Techniques; Genetic Predisposition to Disease; Genetics/Genomes/Proteomics/Metabolomics; HEK293 Cells; Humans; I-kappa B Kinase - immunology; Interleukin-2 - genetics; Interleukin-2 - immunology; Jurkat Cells; Leukocytes, Mononuclear - immunology; MAP Kinase Kinase Kinases - immunology; NF-kappa B - immunology; Polymerase Chain Reaction; Receptors, Antigen, T-Cell - immunology; Signal Transduction - genetics; Signal Transduction - immunology; Ubiquitin - immunology
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db16-1023

Although over 40 type 1 diabetes (T1D) risk loci have been mapped in humans, the causative genes and variants for T1D are largely unknown. Here, we investigated a candidate gene in the 21q22.3 risk locus- , which is primarily expressed in T cells where it is thought to play a largely redundant role. Genetic variants in have been shown to be associated with several autoimmune diseases in addition to T1D. However, the molecular mechanism underlying these genetic associations is unresolved. Our study reveals a previously unrecognized role of UBASH3A in human T cells: UBASH3A attenuates the NF-κB signal transduction upon T-cell receptor (TCR) stimulation by specifically suppressing the activation of the IκB kinase complex. We identify novel interactions of UBASH3A with nondegradative polyubiquitin chains, TAK1 and NEMO, suggesting that UBASH3A regulates the NF-κB signaling pathway by an ubiquitin-dependent mechanism. Finally, we show that risk alleles at rs11203203 and rs80054410, two T1D-associated variants in , increase expression in human primary CD4 T cells upon TCR stimulation, inhibiting NF-κB signaling via its effects on the IκB kinase complex and resulting in reduced gene expression.