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Cited by 39interferon and immune responsesTelomeres, Telomerase, and SenescenceChromosomal and Genetic Variations

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

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Di Giorgio, Eros, Xodo, Luigi E.·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.917998PMC PMC9218063
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Abstract

Bi-directional transcription of Human Endogenous Retroviruses (hERVs) is a common feature of autoimmunity, neurodegeneration and cancer. Higher rates of cancer incidence, neurodegeneration and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties. What is clearly accepted, instead, is the impact of the re-activation of dormant hERV on the maintenance of stemness and tissue self-renewing properties. An innate cellular immunity system, based on the RLR-MAVS circuit, controls the degradation of dsRNAs arising from the transcription of hERV elements, similarly to what happens for the accumulation of cytoplasmic DNA leading to the activation of cGAS/STING pathway. While agonists and inhibitors of the cGAS–STING pathway are considered promising immunomodulatory molecules, the effect of the RLR-MAVS pathway on innate immunity is still largely based on correlations and not on causality. Here we review the most recent evidence regarding the activation of MDA5-RIG1-MAVS pathway as a result of hERV de-repression during aging, immunosenescence, cancer and autoimmunity. We will also deal with the epigenetic mechanisms controlling hERV repression and with the strategies that can be adopted to modulate hERV expression in a therapeutic perspective. Finally, we will discuss if the RLR-MAVS signalling pathway actively modulates physiological and pathological conditions or if it is passively activated by them.

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  • Retrotransposon-derived eccDNA and dsRNA can initiate an antiviral response through detection by cGAS-STING, Toll-like receptors, RIG-I, and MDA5, resulting in production of type I interferons and proinflammatory cytokines.

    “Retrotransposon-derived eccDNA ( Figure 2a ) and dsRNA ( Figure 2b ) can initiate an antiviral response through their detection by the cytosolic DNA–sensing pathway mediated by cGAS-STING and nucleic acid–sensing Toll-like receptors (TLRs), as well as viral RNA sensors such as retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5, a RIG-I-like receptor),”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Di Giorgio & Xodo 2022

    The “ERVs Intracellular Sensing and Signaling” section identifies TLR3 as a dsRNA sensor, cGAS as a cytoplasmic DNA sensor, and RIG-I-like receptors as sensors of retroviral dsRNA. The “dsRNA Detection” section links repetitive-element dsRNA to MDA5 activation and a type I interferon response. The paper does not specifically identify retrotransposon-derived eccDNA as a cGAS-STING trigger, so that part of the claim is not supported. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Di Giorgio, E., & Xodo, L. E.
Affiliations
University of Udine (IT)
Corresponding author
Xodo, Luigi E.
ORCID
Xodo, Luigi E.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-06-09
Volume
13
Pages
917998-917998
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2022.917998
PMC
PMC9218063
OpenAlex
W4285742129
Cited by
39
References
10
Citations by year
2026: 7 · 2025: 7 · 2024: 11 · 2023: 11 · 2022: 3
FWCI
0.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Research Information System (University of Udine) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Associazione Italiana per la Ricerca sul Cancro
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
Keywords
endogenous retroviruses, RIG-I-like receptors, MAVS, MDA5, RIG-I, immunosenescence, aging, senescence, innate immunity, cGAS-STING pathway, epigenetic silencing, autoimmunity, cancer, stemness, immunomodulatory therapy
MeSH terms
Aged, Aging, Humans, Immunity, Innate, Neoplasms, Signal Transduction, Endogenous Retroviruses

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