Lupus-associated endogenous retroviral LTR polymorphism and epigenetic imprinting promote HRES-1/RAB4 expression and mTOR activation
Aparna Godavarthy, … , Katalin Banki, Andras Perl
Aparna Godavarthy, … , Katalin Banki, Andras Perl
Published December 5, 2019
Citation Information: JCI Insight. 2020;5(1):e134010. https://doi.org/10.1172/jci.insight.134010.
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Research Article Immunology

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

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.

Authors

Aparna Godavarthy, Ryan Kelly, John Jimah, Miguel Beckford, Tiffany Caza, David Fernandez, Nick Huang, Manuel Duarte, Joshua Lewis, Hind J. Fadel, Eric M. Poeschla, Katalin Banki, Andras Perl

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Figure 10

Schematic diagram of transcriptional regulation of HRES-1 expression and its effect on T cell activation.

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Schematic diagram of transcriptional regulation of HRES-1 expression and...
Promoter activity is controlled by binding of NRF1 and USF1 to nucleotides –50 to –67 (site 1) and –114 to –124 (site 2), respectively. NRF1 binds to site 1 when demethylated at cytosine–51 while it only binds site 2 when it is methylated at cytosine–119. Alternatively, USF1 only binds site 2 when cytosine–119 is methylated. Expression of HRES-1/Rab4 is enhanced by the LTR in intron 1. LTR enhancer activity is regulated by transcription factors IRF2, PSIP1, IRF, SFRS3, SFRS5, and HSBP1. As earlier documented, IRF1 interacts with HIV-tat (62). Binding of IRF2 and PSIP1 is influenced by the SNP rs451401 with CC alleles promoting IRF2, while GG alleles promote PSIP1 activity in a cell type–specific manner. HRES1/Rab4 expression is elevated in PBLs from human subjects with rs451401 CC alleles relative to those with GG alleles with and without TCR stimulation. Human subjects with rs451401 CC alleles show enhanced CD3/CD28 costimulation-induced activation of mTORC1 and transcription factors that regulate the expression of HRES-1/Rab4. Inactivation of DNMT1 promotes the expression of HRES-1/Rab4. Methylation is reduced within the LTR enhancer and site 1 (cytosine–51) of the promoter, while it is increased in site 2 (cytosine–119) of the promoter in patients with SLE that all favor overexpression of HRES-1/Rab4. HRES-1/Rab4 mediates the endocytic recycling and lysosomal degradation of CD4, CD3ζ, and Drp1 (21, 22). The loss of Drp1 blocks mitophagy and promotes the accumulation of oxidative stress–generating mitochondria (22, 63). The resultant oxidative stress activates mTORC1 and inhibits DNMT1. Moreover, the loss of CD3ζ leads to compensatory accumulation of FcεRIγ (21), which enhances TCR-mediated signal transduction (64). Thus, human subjects with rs451401 CC alleles accommodate a positive feedback loop involving TCR signal transduction, mTOR activation, and DNMT1 inhibition, which synergistically promote the overexpression of HRES-1/Rab4.