Inflammatory T cells contribute to the pathogenesis of the autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed UHRF-X as a novel SLE biomarker. T-cell-specific UHRF-X transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHRF-X prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF-X transgenic mice were obliterated by MAP4K3 knockout. Furthermore, UHRF-X protein was indeed overexpressed in peripheral blood T cells of SLE patients. Collectively, UHRF-X overexpression in T cells inhibits the E3 ligase function of UHRF1 and induces IL-17A-mediated autoimmune responses. This report unveils a novel gene that can block UHRF1 function, leading to autoimmune disease.
Date:
2024-05-01
Relation:
Journal of Immunology. 2024 May 01;212(1, Suppl.):Meeting Abstract 020-5291.
