Trex1 prevents cell-intrinsic initiation of autoimmunity

By Daniel B. Stetson, J. S. Ko, T. Heidmann, R. Medzhitov. Cell, 2008

1,242 citations recorded by the source corpus.

SUMMARY 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 interferon-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.

Subfields: Immunology, Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/e4848d637fee5038fe59823d1c1ac12211d667e2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Shizuo Akira
2. Taro Kawai
3. Zhijian J. Chen
4. O. Takeuchi
5. R. Medzhitov
6. Tuo Li
7. Y. Chiu
8. J. Cox

In Molecular Biology

1. Shizuo Akira
2. Taro Kawai
3. Zhijian J. Chen
4. O. Takeuchi
5. J. Cox
6. R. Watson
7. P. Manzanillo
8. Tuo Li

In Rheumatology

1. Zhijian J. Chen
2. Haig H. Kazazian
3. J. Goodier
4. Shizuo Akira

Citations in the corpus

• Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. (2014, background): “Accumulation of transposable elements can result in autoimmunity with elevated ISGs in normal tissue (Stetson et al., 2008).”
• Innate Immunity to Virus Infection (2009, background): “In addition, loss of exonuclease 1 (Trex1) resulted in accumulation of ssDNA derived from endogenous retroelements, leading to the development of autoimmune diseases such as Aicardi–Goutieres syndrome (AGS) via production of type I IFNs (108).”
• HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (2011, background): “and it has been proposed that TREX1 functions in the clearing of reverse transcripts produced from endogenous retroviral element”
• Pattern recognition receptors and inflammation. (2010, background): “It has been shown that DNA derived from endogenous retroelements accumulates in Trex1 / cells and stimulates the induction of IFN-inducible genes (Stetson et al., 2008).”
• The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors (2010, background): “Loss of TREX1 in cells results in the accumulation of DNA derived from retro elements, which are responsible for the induction of interferon response”
• A census of human RNA-binding proteins (2014, background): “family (ERI1-3), the ISG20 family (ISG20, ISG20L2, AEN), and the ssDNA/ssRNA-specific TREX1 family involved in ssDNA 3’ end repair (TREX1-2) (Stetson et al., 2008; Yuan et al., 2015).”
• DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. (2015, background): “Notably, accumulation of cytoplasmic ssDNA due to defects in the DNA exonuclease TREX1 (Stetson et al., 2008), or the 30 exonuclease and deoxynucleotide (dNTP) triphosphohydrolase SAMHD1 (Behrendt et al.”
• An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome (2009, background): “Trex1 is proposed to remove retroviral DNA to prevent erroneous activation of the IFN-β pathwa”