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Editorial
. 2016 Nov;68(11):2568-2570.
doi: 10.1002/art.39794.

Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity

Andras Perl  1
Affiliations
Editorial

Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity

Andras Perl. Arthritis Rheumatol. 2016 Nov.
No abstract available

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Figures

Figure 1
Figure 1
Mechanistic diagram of endogenous retrovirus (ERV)–regulated endosomal recycling in autoimmune diseases. ERVs and other retroelements are integrated into the nuclear DNA. ERVs are transcribed into RNA by RNA polymerase II (RNA pol II). In turn, retroviral transcripts can be reverse transcribed into DNA using transfer RNA (tRNA) as a primer. While most ERVs are transcriptionally silent, as a rare example, human T lymphotropic virus–related endogenous sequence 1 (HRES‐1) is transcribed into RNA and translated into protein, such as HRES‐1/Rab4 (4). This small GTPase promotes the recycling and lysosomal degradation of cell surface receptors, such as CD4 (4), CD3ζ 5, and Drp1 (6). The HRES‐1/Rab4–mediated depletion of dynamin‐related protein 1 (Drp1) inhibits mitochondrial fission and causes the accumulation of mitochondria that results in increased production of reactive oxygen intermediates (ROIs) in lupus T cells 6. Thus, the accumulation of mitochondria may underlie oxidative stress in patients with systemic lupus erythematosus 8. TLR‐7 = Toll‐like receptor 7; LINE‐1 = long interspersed nuclear element 1; PBS = primer binding site.
Figure 2
Figure 2
Mechanisms of ERV‐activated interferon (IFN) production in autoimmunity. The human genome harbors retroelements, such as LINE‐1. They can be reverse transcribed into DNA and metabolized by TREX1 (the three prime repair exonuclease 1 gene), which is deficient in patients with Aicardi‐Goutières syndrome and chilblain lupus 11. Increased transcription of LINE‐1 is now recognized as an important trigger of IFN production, which is mediated through RNA sensing, and it involves signal transduction through TLR‐7/TLR‐8, cGMP–cAMP synthase (cGAS), retinoic acid–inducible gene 1 (RIG‐1), and NF‐κB. Alternatively, reverse transcribed ERV DNA is recognized via TLR‐9, which also traffics through endosomes 23. Moreover, mitochondrial oxidative stress activates the mitochondrial antiviral signaling protein (MAVS), which acts as an amplifier of RIG‐1 activation during IFN signaling 14. Oxidative stress also causes DNA hypomethylation 16, a process that underlies increased LINE‐1 expression 15. In addition to promoting nucleic acid–driven IFN production, ERV Gag‐encoded proteins, such as HRES‐1/p28, or the LINE‐1 p40 protein may also contribute to autoimmunity via molecular mimicry 22. See Figure 1 for other definitions.
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Comment on

References

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