Epigenetic activation of the TUSC3 gene as a potential therapy for XMEN disease

Haodong Ding; Yuwei Li; Maoxin Fang; Jiaojiao Chen; Lipin Liu; Zhigang Lu; Jia Hou; Min Luo

doi:10.1016/j.jaci.2023.04.003

Epigenetic activation of the TUSC3 gene as a potential therapy for XMEN disease

J Allergy Clin Immunol. 2023 Jun;151(6):1622-1633.e10. doi: 10.1016/j.jaci.2023.04.003. Epub 2023 Apr 21.

Authors

Haodong Ding¹, Yuwei Li¹, Maoxin Fang¹, Jiaojiao Chen¹, Lipin Liu², Zhigang Lu³, Jia Hou⁴, Min Luo⁵

Affiliations

¹ Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
² Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China.
³ Fifth People's Hospital of Shanghai, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: zhiganglu@fudan.edu.cn.
⁴ Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China. Electronic address: doctorhoujia@hotmail.com.
⁵ Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: luo_min@fudan.edu.cn.

PMID: 37086924
DOI: 10.1016/j.jaci.2023.04.003

Abstract

Background: X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus infection and N-linked glycosylation defect (XMEN) disease is a rare combined immunodeficiency caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. MAGT1 deficiency impairs magnesium transport and the N-linked glycosylation of a panel of proteins, which subsequently abolishes the expression of key immune receptors such as natural killer group 2, member D (aka NKG2D). These effects induce immune system abnormalities, chronic Epstein-Barr virus infection, and neoplasia. Recent research shows that MAGT1 and tumor candidate suppressor 3 (TUSC3) share high sequence and functional similarity.

Objective: We sought to investigate the feasibility of activating TUSC3 expression to provide a potential therapeutic strategy for XMEN disease.

Methods: The expression profiles of MAGT1 and TUSC3 were analyzed using multiple databases, real-time quantitative PCR, and Western blot. The effects of decitabine and panobinostat on the regulation of TUSC3 expression were explored in both MAGT1 knockout (KO)/patient-derived lymphocytes and MAGT1 KO hepatocytes.

Results: Although TUSC3 is widely expressed, it is undetectable specifically in the immune system and liver, consistent with the main diseased tissues in patients with XMEN disease. CRISPR/Cas9-mediated KO of MAGT1 in the NKL cell line successfully mimicked the phenotypes of XMEN patient-derived lymphocytes, and exogenous expression of TUSC3 rescued the deficiencies in KO NKL cells. Using this in vitro model, we identified 2 epigenetic drugs, decitabine and panobinostat, by screening. Combination treatment using these 2 drugs significantly upregulated TUSC3 expression and rescued the immune and liver abnormalities.

Conclusions: Epigenetic activation of TUSC3 expression constitutes an effective therapeutic strategy for XMEN disease.

Keywords: MAGT1; NKG2D; TUSC3; XMEN; cytotoxicity; epigenetic drugs; liver abnormality.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Decitabine
Epigenesis, Genetic
Epstein-Barr Virus Infections* / genetics
Herpesvirus 4, Human
Humans
Magnesium* / metabolism
Panobinostat

Substances

Magnesium
Decitabine
Panobinostat