Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling Journal Article
| Authors: | Shim, A.; Luan, X.; Zhou, W.; Crow, Y. J.; Maciejowski, J. |
| Article Title: | Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling |
| Abstract: | 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-Goutières syndrome (AGS). Despite key roles in regulating cGAS-STING and suppressing excessive inflammation, the impact of many disease-associated TREX1 mutations - particularly those outside of the core catalytic domains - remains 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. © 2024 The Author(s). Published by Oxford University Press. All rights reserved. |
| Keywords: | signal transduction; controlled study; protein phosphorylation; unclassified drug; genetics; mutation; nonhuman; mutant protein; protein localization; protein motif; metabolism; gene overexpression; stat1 protein; gene amplification; protein stability; membrane proteins; gene locus; enzyme activity; wild type; immunoregulation; endoplasmic reticulum; regulatory mechanism; messenger rna; membrane protein; western blotting; phosphoproteins; cellular distribution; innate immunity; systemic lupus erythematosus; alanine; exonuclease; phosphoprotein; cell mutant; amino acid motifs; cell lysate; proline; exodeoxyribonuclease; exodeoxyribonucleases; nucleotidyltransferase; hek293 cells; lupus erythematosus, systemic; nucleotidyltransferases; interferon regulatory factor 3; autoimmune diseases of the nervous system; dna transfection; humans; human; article; protein aggregate; aicardi-goutieres syndrome; nervous system malformations; mcf-10a cell line; trex1; cgas sting signaling; hek293s cell line; trex1 protein; sting1 protein, human; three prime repair exonuclease 1; cgas-sting; polyproline helix; cgas protein, human; autoimmune disease of the nervous system; nervous system malformation |
| Journal Title: | Human Molecular Genetics |
| Volume: | 33 |
| Issue: | 18 |
| ISSN: | 0964-6906 |
| Publisher: | Oxford University Press |
| Date Published: | 2024-09-15 |
| Start Page: | 1555 |
| End Page: | 1566 |
| Language: | English |
| DOI: | 10.1093/hmg/ddae089 |
| PUBMED: | 38796715 |
| PROVIDER: | scopus |
| PMCID: | PMC11373327 |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding author is John Maciejowski -- Source: Scopus |
