Trex1 prevents cell-intrinsic initiation of autoimmunity.

Cell
Daniel B StetsonRuslan Medzhitov

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.

References

Oct 6, 1998·Annual Review of Biochemistry·G R StarkR D Schreiber
Jul 3, 1999·The Journal of Biological Chemistry·D J Mazur, F W Perrino
Nov 5, 1999·Trends in Microbiology·J P Stoye
Mar 31, 2000·Nature Genetics·C EsnaultT Heidmann
Jun 3, 2000·Nature Genetics·M NapireiT Möröy
Aug 2, 2001·Nature Genetics·K YasutomoY Kuroda
Nov 9, 2001·Annual Review of Genetics·E M Ostertag, H H Kazazian
Apr 12, 2002·Nature·Elizabeth A LeadbetterAnn Marshak-Rothstein
May 4, 2002·Nature Reviews. Molecular Cell Biology·Igor V Shevelev, Ulrich Hübscher
Dec 24, 2002·Current Opinion in Immunology·Shizuo Akira
Jan 14, 2003·Annual Review of Immunology·Kiyoshi TakedaShizuo Akira
Feb 1, 2003·Molecular Pathology : MP·P N NelsonP G Murray
May 13, 2003·BMC Genomics·Chih Long LiuBradley E Bernstein
Apr 27, 2004·Nature Genetics·Marie DewannieuxThierry Heidmann
Jul 16, 2004·Molecular and Cellular Biology·Masashi MoritaDeborah E Barnes
Nov 30, 2004·Nature Immunology·Hideyuki YoshidaShigekazu Nagata
Feb 16, 2005·Nature·Oliver SchulzCaetano Reis e Sousa
Mar 18, 2005·Annual Review of Immunology·Argyrios N TheofilopoulosDwight H Kono
May 5, 2005·The Journal of Pediatrics·A SanchisM L Martínez-Frías
Nov 23, 2005·The Journal of Experimental Medicine·Yasutaka OkabeShigekazu Nagata
Jan 18, 2006·Immunity·Daniel B Stetson, Ruslan Medzhitov
May 20, 2006·Science·Prapaporn PisitkunSilvia Bolland
Jun 17, 2006·Proceedings of the National Academy of Sciences of the United States of America·Srividya SubramanianEdward K Wakeland
Jun 21, 2006·The Journal of Experimental Medicine·Himanshu KumarShizuo Akira
Jul 29, 2006·Nature Genetics·Marta E Alarcón-Riquelme
Sep 19, 2006·Immunity·Daniel B Stetson, Ruslan Medzhitov
Oct 3, 2006·Current Opinion in Immunology·Virginia PascualJacques Banchereau
Nov 23, 2006·Infectious Disease Clinics of North America·Ines Colmegna, Robert F Garry
Apr 19, 2007·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Min Ae Lee-KirschNorbert Hubner
Jul 17, 2007·Cell·Christopher C Goodnow

❮ Previous
Next ❯

Citations

Dec 17, 2010·Cellular and Molecular Life Sciences : CMLS·Hiroki Ishikawa, Glen N Barber
Nov 27, 2008·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Fred W PerrinoThomas Hollis
Feb 2, 2013·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Victoria TünglerMin Ae Lee-Kirsch
Jun 8, 2013·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Björn Rabe
Jan 6, 2010·Cancer Immunology, Immunotherapy : CII·David SavitskyTadatsugu Taniguchi
May 11, 2010·Biogerontology·Mauro ProvincialiElisa Pierpaoli
Oct 12, 2012·Journal of Clinical Immunology·Hyon Ju Park, John P Atkinson
Nov 19, 2013·Best Practice & Research. Clinical Rheumatology·Clara Malattia, Alberto Martini
Apr 4, 2013·Cytokine & Growth Factor Reviews·Markus J Hofer, Iain L Campbell
Jun 4, 2013·Trends in Microbiology·Claudia Gürtler, Andrew G Bowie
Sep 22, 2010·Quarterly Reviews of Biophysics·Wei Yang
Jun 5, 2013·Cell Research·Xiaoyu PanOliver T Fackler
Mar 21, 2012·Immunology and Cell Biology·Kerstin KieferAnn Marshak-Rothstein
Mar 28, 2012·Immunology and Cell Biology·Taner CavlarVeit Hornung
Aug 9, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Judith AgudoBrian D Brown
Nov 19, 2010·Nature·Xiaoxuan QiChangjiang Dong
Feb 3, 2011·Nature Communications·Leonora BalajJohan Skog
Jan 23, 2009·Nature Immunology·Tilmann BürckstümmerGiulio Superti-Furga
Dec 18, 2009·Nature Immunology·Alexander V Chervonsky
Feb 22, 2012·Nature Immunology·Nan Yan, Zhijian J Chen
Mar 21, 2012·Nature Immunology·Vijay A K RathinamKatherine A Fitzgerald
Oct 21, 2010·Nature Immunology·Teunis B H Geijtenbeek
Apr 2, 2009·Nature Reviews. Genetics·Isaac T W HarleyJennifer A Kelly
Aug 19, 2011·Nature Reviews. Genetics·Henry L Levin, John V Moran
Jan 26, 2010·Nature Reviews. Immunology·Veit Hornung, Eicke Latz
Sep 15, 2012·Nature Reviews. Immunology·Nisha K Duggal, Michael Emerman
Mar 17, 2011·Nature Reviews. Microbiology·Ellen F Foxman, Akiko Iwasaki
Feb 10, 2010·Nature Reviews. Rheumatology·Argyrios N TheofilopoulosRoberto Baccala
Nov 10, 2010·Nature Reviews. Rheumatology·Yun Deng, Betty P Tsao
Jun 5, 2013·Nature Reviews. Rheumatology·José C CrispínGeorge C Tsokos
Jan 12, 2010·Nature Structural & Molecular Biology·Mark D StengleinReuben S Harris
Feb 5, 2013·Nature Structural & Molecular Biology·Benjamin HerquelIrwin Davidson
Sep 3, 2013·Nature Structural & Molecular Biology·Sara R HerasJavier F Cáceres
Nov 20, 2009·Proceedings of the National Academy of Sciences of the United States of America·Gabriele B Beck-EngeserMatthias Wabl
Nov 21, 2009·Proceedings of the National Academy of Sciences of the United States of America·Tatsuya SaitohShizuo Akira
Mar 4, 2011·Proceedings of the National Academy of Sciences of the United States of America·Rodolphe SuspèneSimon Wain-Hobson

❮ Previous
Next ❯

Related Concepts

Related Feeds

Aminoglycosides (ASM)

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Aminoglycosides

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Cell eTOC

Cell is a scientific journal publishing research across a broad range of disciplines within the life sciences field. Discover the latest research from Cell here.