Trex1 prevents cell-intrinsic initiation of autoimmunity
Open accessAbstract
Detection of nucleic acids and induction of type I interferons (IFNs) are principal elements of antiviral defense but can cause autoimmunity if misregulated. Cytosolic DNA detection activates a potent, cell-intrinsic antiviral response through a poorly defined pathway. In a screen for proteins relevant to this IFN-stimulatory DNA (ISD) response, we identify 3' repair exonuclease 1 (Trex1). Mutations in the human trex1 gene cause Aicardi-Goutieres syndrome (AGS) and chilblain lupus, but the molecular basis of these diseases is unknown. We define Trex1 as an essential negative regulator of the ISD response and delineate the genetic pathway linking Trex1 deficiency to lethal autoimmunity. We show that single-stranded DNA derived from endogenous retroelements accumulates in Trex1-deficient cells, and that Trex1 can metabolize reverse-transcribed DNA. These findings reveal a cell-intrinsic mechanism for initiation of autoimmunity, implicate the ISD pathway as the cause of AGS, and suggest an unanticipated contribution of endogenous retroelements to autoimmunity.
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Retrotransposon DNA was present in cytoplasmic fractions of hearts from TREX1 mutant mice, with L1, SINE, and LTR retrotransposon DNAs significantly enriched compared to normal mice.
“Pioneering work by Stetson et at.53 found that retrotransposon DNA was present in the cytoplasmic fractions of hearts from TREX1 mutant mice. Sequencing showed that L1, SINE, and LTR retrotransposon DNAs were significantly enriched compared to normal mice.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [53]
In Results, ‘Identification of endogenous Trex1 DNA substrates’ (page unavailable), the authors describe extracting DNA from hearts under conditions intended to minimize extraction of organelles. They report retroelement-derived fragments among Trex1-knockout heart clones but not wild-type clones, including 12 L1, 10 LTR, and 3 SINE sequences. The copy does not establish that each of the three classes was statistically significantly enriched, so ‘significantly’ overstates the reported comparison. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTREX1 degrades cytoplasmic L1 DNA and its loss initiates a cGAS/STING response.
“TREX1 degrades cytoplasmic L1 DNA53 and its loss initiates a cGAS/STING response.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [53]
The citation is attached to the L1 DNA clause, not the subsequent cGAS/STING clause. In Results (“Identification of endogenous Trex1 DNA substrates” and “Trex1 metabolizes DNA of endogenous retroelements”), L1-derived DNA accumulates in Trex1-deficient mouse hearts, and Trex1 reduces L1 retrotransposition. The paper does not establish that the L1 DNA Trex1 degrades is cytoplasmic; the Discussion says L1 reverse transcription is thought to occur in the nucleus. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn normal cells, cytoplasmic DNases DNase2 and TREX1 degrade double-stranded and single-stranded DNA in the cytoplasm to prevent activation of the innate immune response.
“In normal cells, the cytoplasmic DNases, DNase2 and TREX1, degrade the double‐stranded and single‐stranded DNA in the cytoplasm to prevent activation of the innate immune response.71, 72”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [71]
The Results and Discussion support TREX1’s role in clearing cytosolic single-stranded DNA and limiting an innate immune response. But the Introduction calls DNase II lysosomal, not cytoplasmic, and the Discussion identifies TREX1 as a single-stranded DNA exonuclease; this paper does not support the sentence’s description of both enzymes as cytoplasmic DNases degrading both forms of DNA. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAnalysis of Trex1-deficient mice has revealed accumulation of cytosolic DNA fragments derived from reverse-transcription of endogenous REs.
“Indeed, analysis of Trex1-deficient mice has revealed accumulation of cytosolic DNA fragments derived from reverse-transcription of endogenous REs 28.”
From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [28]
In Results, the authors report that DNA fragments from endogenous retroelements were abundant in Trex1-deficient mouse hearts and suggest that these fragments accumulate within heart cells. In the Discussion, they propose that the DNA is reverse-transcribed; they do not establish that origin or directly show that the retroelement-derived fragments are cytosolic. (LLM, conf=0.86)
Experimental — accuracy not yet measuredL1 cDNA has been found in the cytosol in certain conditions, such as autoimmunity.
“Although TPRT occurs in the nucleus, L1 cDNA has also been found in the cytosol in certain conditions, such as autoimmunity (Stetson et al., 2008; Thomas et al., 2017), and others which will be discussed in more detail below.”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Stetson et al., 2008
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- Authors
- Stetson, D. B., Ko, J. S., Heidmann, T., & Medzhitov, R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Stetson, Daniel B.
- Medzhitov, Ruslan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 134
- Issue
- 4
- Pages
- 587-598
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2626626
- OpenAlex
- W2167317609
- Cited by
- 1,280
- References
- 59
- Citations by year
- 2026: 50 · 2025: 70 · 2024: 78 · 2023: 49 · 2022: 73 · 2021: 78 · 2020: 69 · 2019: 75 · 2018: 71 · 2017: 80 · 2016: 67 · 2015: 84 · 2014: 82 · 2013: 94 · 2012: 81
- FWCI
- 24.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research Institute
- National Institutes of Health (1K99AI072945-01A1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TREX1, autoimmunity, Aicardi-Goutières syndrome, chilblain lupus, type I interferon, cytosolic DNA sensing, endogenous retroelements, single-stranded DNA, reverse transcription, antiviral defense
- MeSH terms
- Animals, Autoantibodies, Cell Line, DNA, Single-Stranded, Exodeoxyribonucleases, Humans, Interferon Type I, Phosphoproteins, Autoimmunity, Retroelements, Mice
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