{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:47:15Z","timestamp":1789541235461,"version":"build-2803163510"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T00:00:00Z","timestamp":1716595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R37CA261183"],"award-info":[{"award-number":["R37CA261183"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000875","name":"Pew Charitable Trusts","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000875","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000983","name":"Mary Kay Ash Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000983","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MSKCC Frank A. Howard Fellowship"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The cGAS-STING pathway detects cytosolic DNA and activates a signaling cascade that results in a type I interferon (IFN) response. The endoplasmic reticulum (ER)-associated exonuclease TREX1 suppresses cGAS-STING by eliminating DNA from the cytosol. Mutations that compromise TREX1 function are linked to autoinflammatory disorders, including systemic lupus erythematosus (SLE) and Aicardi-Gouti\u00e8res syndrome (AGS). Despite key roles in regulating cGAS-STING and suppressing excessive inflammation, the impact of many disease-associated TREX1 mutations\u2014particularly those outside of the core catalytic domains\u2014remains poorly understood. Here, we characterize a recessive AGS-linked TREX1 P61Q mutation occurring within the poorly characterized polyproline helix (PPII) motif. In keeping with its position outside of the catalytic core or ER targeting motifs, neither the P61Q mutation, nor aggregate proline-to-alanine PPII mutation, disrupts TREX1 exonuclease activity, subcellular localization, or cGAS-STING regulation in overexpression systems. Introducing targeted mutations into the endogenous TREX1 locus revealed that PPII mutations destabilize the protein, resulting in impaired exonuclease activity and unrestrained cGAS-STING activation. Overall, these results demonstrate that TREX1 PPII mutations, including P61Q, impair proper immune regulation and lead to autoimmune disease through TREX1 destabilization.<\/jats:p>","DOI":"10.1093\/hmg\/ddae089","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T16:59:35Z","timestamp":1716397175000},"page":"1555-1566","source":"Crossref","is-referenced-by-count":11,"title":["Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling"],"prefix":"10.1093","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5351-0774","authenticated-orcid":false,"given":"Abraham","family":"Shim","sequence":"first","affiliation":[{"name":"Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center , 430 East 67th Street, New York, NY 10065,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohan","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology , School of Life Sciences, , 1088 Xueyuan Avenue, Shenzhen, GD 518055,","place":["China"]},{"name":"Southern University of Science and Technology , School of Life Sciences, , 1088 Xueyuan Avenue, Shenzhen, GD 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology , School of Life Sciences, , 1088 Xueyuan Avenue, Shenzhen, GD 518055,","place":["China"]},{"name":"Southern University of Science and Technology , School of Life Sciences, , 1088 Xueyuan Avenue, Shenzhen, GD 518055,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanick J","family":"Crow","sequence":"additional","affiliation":[{"name":"MRC Human Genetics Unit , Institute of Genetics and Cancer, , Crewe Road South, Edinburgh,","place":["United Kingdom"]},{"name":"The University of Edinburgh , Institute of Genetics and Cancer, , Crewe Road South, Edinburgh,","place":["United Kingdom"]},{"name":"Laboratory of Neurogenetics and Neuroinflammation , Imagine Institute, INSERM UMR1163, , 24 Boulevard du Montparnasse, 75015 Paris,","place":["France"]},{"name":"University Paris Cit\u00e9 , Imagine Institute, INSERM UMR1163, , 24 Boulevard du Montparnasse, 75015 Paris,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Maciejowski","sequence":"additional","affiliation":[{"name":"Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center , 430 East 67th Street, New York, NY 10065,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,25]]},"reference":[{"key":"2026041405070314800_ref1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41577-021-00633-9","article-title":"The type I interferonopathies: 10 years on","volume":"22","author":"Crow","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"2026041405070314800_ref2","doi-asserted-by":"crossref","first-page":"31649","DOI":"10.1074\/jbc.M806155200","article-title":"The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease","volume":"283","author":"Lehtinen","year":"2008","journal-title":"J Biol Chem"},{"key":"2026041405070314800_ref3","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1086\/513443","article-title":"Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome","volume":"80","author":"Rice","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2026041405070314800_ref4","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1086\/521373","article-title":"Clinical and molecular phenotype of Aicardi-Goutieres syndrome","volume":"81","author":"Rice","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2026041405070314800_ref5","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/ajmg.a.36887","article-title":"Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1","volume":"167A","author":"Crow","year":"2015","journal-title":"Am J Med Genet A"},{"key":"2026041405070314800_ref6","doi-asserted-by":"crossref","first-page":"5993","DOI":"10.4049\/jimmunol.1400737","article-title":"TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner","volume":"192","author":"Ablasser","year":"2014","journal-title":"J Immunol"},{"key":"2026041405070314800_ref7","doi-asserted-by":"crossref","first-page":"17022","DOI":"10.1074\/jbc.M100623200","article-title":"Excision of 3\u2032 termini by the Trex1 and TREX2 3\u2032\u2192 5\u2032 exonucleases characterization of the recombinant proteins","volume":"276","author":"Mazur","year":"2001","journal-title":"J Biol Chem"},{"key":"2026041405070314800_ref8","doi-asserted-by":"crossref","first-page":"5117","DOI":"10.1073\/pnas.1423804112","article-title":"Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease","volume":"112","author":"Grieves","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026041405070314800_ref9","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.4049\/jimmunol.1500969","article-title":"Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi\u2013Gouti\u00e8res syndrome","volume":"195","author":"Gray","year":"2015","journal-title":"J Immunol"},{"key":"2026041405070314800_ref10","doi-asserted-by":"crossref","first-page":"11752","DOI":"10.1038\/ncomms11752","article-title":"RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA","volume":"7","author":"Wolf","year":"2016","journal-title":"Nat Commun"},{"key":"2026041405070314800_ref11","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.cell.2008.06.032","article-title":"Trex1 prevents cell-intrinsic initiation of autoimmunity","volume":"134","author":"Stetson","year":"2008","journal-title":"Cell"},{"key":"2026041405070314800_ref12","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nature12306","article-title":"cGAS produces a 2\u2032-5\u2032-linked cyclic dinucleotide second messenger that activates 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