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: 33.12). 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.

0 Followers
 · 
126 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PIWI-interacting RNAs (piRNAs) are a large family of small, single-stranded, non-coding RNAs present throughout the animal kingdom. They form complexes with several members of the PIWI clade of Argonaute proteins and carry out regulatory functions. Their best established biological role is the inhibition of transposon mobilization, which they enforce both at the transcriptional level, through regulation of heterochromatin formation, and by promoting transcript degradation. In this capacity, piRNAs and PIWI proteins are at the heart of the germline cells’ efforts to preserve genome integrity. Additional regulatory roles of piRNAs and PIWI proteins in gene expression are becoming increasingly apparent. PIWI proteins and piRNAs are often detected in human cancers deriving from germline cells as well as somatic tissues. Their detection in cancer correlates with poorer clinical outcomes, suggesting that they play a functional role in the biology of cancer. Nonetheless, the currently available information, while highly suggestive, is still not sufficient to entirely discriminate between a ‘passenger’ role for the ectopic expression of piRNAs and PIWI proteins in cancer from a ‘driver’ role in the pathogenesis of these diseases. In this article, we review some of the key available evidence for the role of piRNAs and PIWI in human cancer and discuss ways in which our understanding of their functions may be improved.
    Journal of Hematology & Oncology 04/2015; 8(1):38. DOI:10.1186/s13045-015-0133-5 · 4.93 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 3.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The DNA damage response (DDR) induces the expression of type I interferons (IFNs), but the underlying mechanisms are poorly understood. Here, we show the presence of cytosolic DNA in different mouse and human tumor cells. Treatment of cells with genotoxic agents increased the levels of cytosolic DNA in a DDR-dependent manner. Cloning of cytosolic DNA molecules from mouse lymphoma cells suggests that cytosolic DNA is derived from unique genomic loci and has the potential to form non-B DNA structures, including R-loops. Overexpression of Rnaseh1, which resolves R-loops, reduced the levels of cytosolic DNA, type I Ifn transcripts, and type I IFN-dependent rejection of lymphoma cells. Live-cell imaging showed a dynamic contact of cytosolic DNA with mitochondria, an important organelle for innate immune recognition of cytosolic nucleotides. In summary, we found that cytosolic DNA is present in many tumor cells and contributes to the immunogenicity of tumor cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; DOI:10.1016/j.celrep.2015.03.041 · 7.21 Impact Factor