Trex1 Prevents Cell-Intrinsic Initiation of Autoimmunity

Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell (Impact Factor: 32.24). 09/2008; 134(4):587-98. DOI: 10.1016/j.cell.2008.06.032
Source: PubMed


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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Available from: Joan Ko, Jul 07, 2014
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    • "One of the few characterized monogenic causes of lupus is a mutation in the gene for the DNase, Trex1, which is known to degrade retroviral complementary DNA (cDNA) (Crow and Rehwinkel, 2009; Yan et al., 2010). The trex1 knockout mouse accumulates nonchromosomal DNA, some derived from retroelements, which drives type I interferon production and autoimmunity (Stetson et al., 2008). Since misplaced DNAs in the cytosol can be sensed by PYHIN family members, whether p202 plays a role in lupus via inhibition of AIM2 response to DNA requires further investigation. "

    • "In AGS the diminished TREX1 DNase activity leads to accumulation of self-DNA from replication debris (Yang et al., 2007) or endogenous retroelements (Stetson et al., 2008), probably contributing to sterile inflammation. However, such etiology does not explain disease caused by C-terminal frameshift mutations. "
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    ABSTRACT: TREX1 is an endoplasmic reticulum (ER)-associated negative regulator of innate immunity. TREX1 mutations are associated with autoimmune and autoinflammatory diseases. Biallelic mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to accumulate, but it is unknown how dominant frameshift (fs) mutations that encode DNase-active but mislocalized proteins cause disease. We found that the TREX1 C terminus suppressed immune activation by interacting with the ER oligosaccharyltransferase (OST) complex and stabilizing its catalytic integrity. C-terminal truncation of TREX1 by fs mutations dysregulated the OST complex, leading to free glycan release from dolichol carriers, as well as immune activation and autoantibody production. A connection between OST dysregulation and immune disorders was demonstrated in Trex1(-/-) mice, TREX1-V235fs patient lymphoblasts, and TREX1-V235fs knock-in mice. Inhibiting OST with aclacinomycin corrects the glycan and immune defects associated with Trex1 deficiency or fs mutation. This function of the TREX1 C terminus suggests a potential therapeutic option for TREX1-fs mutant-associated diseases. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 08/2015; 43(3). DOI:10.1016/j.immuni.2015.07.022 · 21.56 Impact Factor
    • "A reduced activity of Trex1 is associated to major autoimmune and inflammatory diseases such as rheumatoid arthritis (RA) [83]. Mutations in the gene encoding for Trex1 are the cause of the Aicardi-Goutieres syndrome (AGS) [84], of the monogenic chilblain lupus erythematosus [85], and are observed with increased frequency in patients with systemic lupus erythematosus (SLE) [86], suggesting the existence of common pathogenic pathways between these pathologies [82] [87]. The possibility to treat this class of autoimmune disorders by targeting the ERs activity is suggested by results obtained in Trex1-deficient mice, which develop inflammatory myocarditis leading to cardiomyopathy and circulatory failure: the treatment with a combination of RT inhibitors (emtricitabine and tenofovir disoproxil fumarate, two NRTIs, and nevirapine, a NNRTI) targeting L1 reverse transcriptase ameliorates myocarditis [88]. "
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    ABSTRACT: Endogenous retroelements (ERs) represent nearly half of the human genome. Considered up to recent years as "functionless" DNA sequences, they are now known to be involved in important cellular functions such as stress response and generation of non coding regulatory RNAs. Moreover, an increasing amount of data supports the idea of ERs as key players in cellular senescence and in different senescence-related pathogenic cellular processes, including those leading to inflammation, cancer and major age-related multifactorial diseases. The involvement of ERs in these biological mechanisms can suggest new therapeutic strategies in neoplasms, inflammatory/autoimmune diseases and in different age-related pathologies, such as macular degeneration, diabetes, cardiovascular diseases and major age-related neurodegenerative disorders. The therapeutic approaches which can be suggested range from a set of well-known, common drugs that have been shown to modulate ERs activity, to immune therapy against ER-derived tumor antigens, to more challenging strategies such as those based on anti-ERs RNA interference.
    Current drug targets 05/2015; · 3.02 Impact Factor
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