UHRF1P contributes to IL-17A-mediated systemic lupus erythematosus via UHRF1-MAP4K3 axis

Huai-Chia Chuang; Kuei-Yuan Lan; Pu-Ming Hsu; Ming-Han Chen; Yi-Ming Chen; Jeng-Hsien Yen; Ben-Yang Liao; Tse-Hua Tan

doi:10.1016/j.jaut.2024.103221

UHRF1P contributes to IL-17A-mediated systemic lupus erythematosus via UHRF1-MAP4K3 axis

J Autoimmun. 2024 Apr 20:146:103221. doi: 10.1016/j.jaut.2024.103221. Online ahead of print.

Authors

Huai-Chia Chuang¹, Kuei-Yuan Lan², Pu-Ming Hsu¹, Ming-Han Chen³, Yi-Ming Chen⁴, Jeng-Hsien Yen⁵, Ben-Yang Liao⁶, Tse-Hua Tan⁷

Affiliations

¹ Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan.
² Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
³ Division of Allergy, Immunology, and Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan.
⁴ Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.
⁵ Division of Rheumatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁶ Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. Electronic address: liaoby@nhri.edu.tw.
⁷ Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan. Electronic address: ttan@nhri.edu.tw.

PMID: 38643728
DOI: 10.1016/j.jaut.2024.103221

Abstract

Inflammatory T cells contribute to the pathogenesis of 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 the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P 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 UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases.

Keywords: MAP4K3/GLK; SLE; T cells; UHRF1; UHRF1P.