Article

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

ABSTRACT

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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    • "This may then target the mutated retrotransposon DNA for degradation through endonuclease activity. Additionally, the endonucleases TREX1 (Stetson et al., 2008) and ERCC1/XPF (Gasior et al., 2008) can physically cleave the reverse-transcribed cDNA of L1, thereby inhibiting retrotransposition. "
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    ABSTRACT: Retrotransposons are repetitive DNA sequences that are positioned throughout the human genome. Retrotransposons are capable of copying themselves and mobilizing new copies to novel genomic locations in a process called retrotransposition. While most retrotransposon sequences in the human genome are incomplete and incapable of mobilization, the LINE-1 retrotransposon, which comprises~17% of the human genome, remains active. The disruption of cellular mechanisms that suppress retrotransposon activity is linked to the generation of aneuploidy, a potential driver of tumor development. When retrotransposons insert into a novel genomic region, they have the potential to disrupt the coding sequence of endogenous genes and alter gene expression, which can lead to deleterious consequences for the organism. Additionally, increased LINE-1 copy numbers provide more chances for recombination events to occur between retrotransposons, which can lead to chromosomal breaks and rearrangements. LINE-1 activity is increased in various cancer cell lines and in patient tissues resected from primary tumors. LINE-1 activity also correlates with increased cancer metastasis. This review aims to give a brief overview of the connections between LINE-1 retrotransposition and the loss of genome stability. We will also discuss the mechanisms that repress retrotransposition in human cells and their links to cancer.
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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. "

    Full-text · Dataset · Nov 2015
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    • "Among the best characterized of the AGS enzymes is Trex1, a cytosolic DNA exonuclease. Trex1-deficient mice develop lethal autoimmune disease that is entirely dependent on cGAS, STING, the IRF3 transcription factor, the type I IFN receptor, and lymphocytes , thus defining Trex1 as a specific and essential negative regulator of the intracellular DNA-sensing pathway (Ablasser et al., 2014; Gall et al., 2012; Gao et al., 2015; Gray et al., 2015; Stetson et al., 2008). Similarly, SAMHD1 is a dNTP phosphohydrolase that prevents cDNA synthesis by retroviral reverse transcriptase enzymes, strongly suggesting that the cGAS-STING pathway also drives autoimmunity in AGS caused by SAMHD1 mutations (Goldstone et al., 2011; Hrecka et al., 2011; Laguette et al., 2011; Rehwinkel et al., 2013). "
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    ABSTRACT: Mutations in ADAR, which encodes the ADAR1 RNA-editing enzyme, cause Aicardi-Goutières syndrome (AGS), a severe autoimmune disease associated with an aberrant type I interferon response. How ADAR1 prevents autoimmunity remains incompletely defined. Here, we demonstrate that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway. Moreover, we uncovered a MDA5-MAVS-independent function for ADAR1 in the development of multiple organs. We showed that the p150 isoform of ADAR1 uniquely regulated the MDA5 pathway, whereas both the p150 and p110 isoforms contributed to development. Abrupt deletion of ADAR1 in adult mice revealed that both of these functions were required throughout life. Our findings delineate genetically separable roles for both ADAR1 isoforms in vivo, with implications for the human diseases caused by ADAR mutations.
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