Lupus-associated endogenous retroviral LTR polymorphism and epigenetic imprinting promote HRES-1/RAB4 expression and mTOR activation

• Published in: JCI insight Vol. 5; no. 1
• Main Authors: Godavarthy, Aparna, Kelly, Ryan, Jimah, John, Beckford, Miguel, Caza, Tiffany, Fernandez, David, Huang, Nick, Duarte, Manuel, Lewis, Joshua, Fadel, Hind J., Poeschla, Eric M., Banki, Katalin, Perl, Andras
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 16.01.2020
• Subjects: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Aged; Alleles; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Endogenous Retroviruses - genetics; Epigenesis, Genetic; Female; HCT116 Cells; HeLa Cells; Humans; Lupus Erythematosus, Systemic - genetics; Middle Aged; Nuclear Respiratory Factor 1; Receptors, Antigen, T-Cell; T-Lymphocytes; Terminal Repeat Sequences - genetics; Terminal Repeat Sequences - physiology; TOR Serine-Threonine Kinases - genetics; Transcription Factors; Young Adult; Lupus; Immunology; T cells; Rheumatology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.134010

Overexpression and long terminal repeat (LTR) polymorphism of the HRES‑1/Rab4 human endogenous retrovirus locus have been associated with T cell activation and disease manifestations in systemic lupus erythematosus (SLE). Although genomic DNA methylation is diminished overall in SLE, its role in HRES-1/Rab4 expression is unknown. Therefore, we determined how lupus-associated polymorphic rs451401 alleles of the LTR regulate transcription from the HRES-1/Rab4 promoter and thus affect T cell activation. The results showed that cytosine-119 is hypermethylated while cytosine-51 of the promoter and the LTR enhancer are hypomethylated in SLE. Pharmacologic or genetic inactivation of DNA methyltransferase 1 augmented the expression of HRES-1/Rab4. The minimal promoter was selectively recognized by metabolic stress sensor NRF1 when cytosine-119 but not cytosine-51 was methylated, and NRF1 stimulated HRES-1/Rab4 expression in human T cells. In turn, IRF2 and PSIP1 bound to the LTR enhancer and exerted control over HRES-1/Rab4 expression in rs451401 genotype- and methylation-dependent manners. The LTR enhancer conferred markedly greater expression of HRES-1/Rab4 in subjects with rs451401CC over rs451401GG alleles that in turn promoted mechanistic target of rapamycin (mTOR) activation upon T cell receptor stimulation. HRES-1/Rab4 alone robustly activated mTOR in human T cells. These findings identify HRES-1/Rab4 as a methylation- and rs451401 allele-dependent transducer of environmental stress and controller of T cell activation.