Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling

Shim, Abraham1; Luan, Xiaohan2; Zhou, Wen2; Crow, Yanick J.3,4; Maciejowski, John1

2024-05-01

10.1093/hmg/ddae089

HUMAN MOLECULAR GENETICS   影响因子和分区

0964-6906

1460-2083

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 & egrave;res 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.

cGAS-STING TREX1 Aicardi-Goutieres syndrome polyproline helix innate immunity

SCI

英语

其他

National Cancer Institute (NCI)[R37CA261183]

Biochemistry & Molecular Biology ; Genetics & Heredity

Biochemistry & Molecular Biology ; Genetics & Heredity

WOS:001230726300001

OXFORD UNIV PRESS

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Sloan Kettering Inst, Mem Sloan Kettering Canc Ctr, Mol Biol Program, 430 East 67th St, New York, NY 10065 USA
2.Southern Univ Sci & Technol, Sch Life Sci, Dept Immunol & Microbiol, 1088 Xueyuan Ave, Shenzhen 518055, Peoples R China
3.Univ Edinburgh, Inst Genet & Canc, MRC Human Genet Unit, Crewe Rd South, Edinburgh, Scotland
4.Univ Paris Cite, Imagine Inst, Lab Neurogenet & Neuroinflammat, INSERM UMR1163, 24 Blvd Montparnasse, F-75015 Paris, France

Shim, Abraham,Luan, Xiaohan,Zhou, Wen,et al. Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling[J]. HUMAN MOLECULAR GENETICS,2024.

Shim, Abraham,Luan, Xiaohan,Zhou, Wen,Crow, Yanick J.,&Maciejowski, John.(2024).Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling.HUMAN MOLECULAR GENETICS.

Shim, Abraham,et al."Mutations in the non-catalytic polyproline motif destabilize TREX1 and amplify cGAS-STING signaling".HUMAN MOLECULAR GENETICS (2024).