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

JCI Insight. 2020 Jan 16;5(1):e134010. doi: 10.1172/jci.insight.134010.

Abstract

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.

Keywords: Immunology; Lupus; Rheumatology; T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • TOR Serine-Threonine Kinases / genetics*
  • Terminal Repeat Sequences / genetics*
  • Terminal Repeat Sequences / physiology
  • Transcription Factors
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • NRF1 protein, human
  • Nuclear Respiratory Factor 1
  • PSIP1 protein, human
  • Receptors, Antigen, T-Cell
  • Transcription Factors
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases