Language
English
Publication Date
3-12-2025
Journal
Cellular and Molecular Life Sciences
DOI
10.1007/s00018-025-05645-5
PMID
40072623
PMCID
PMC11904002
PubMedCentral® Posted Date
3-12-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Signal peptide peptidase (SPP) is an ER-resident aspartyl intramembrane protease cleaving proteins within type II-oriented transmembrane segments. Here, we identified the tail-anchored protein Three prime repair exonuclease 1 (TREX1) as a novel substrate of SPP. Based on its DNase activity, TREX1 removes cytosolic DNA acting as a negative regulator of the DNA-sensing cGAS/STING pathway. TREX1 loss-of-function variants cause Aicardi-Goutières syndrome (AGS), a type I interferonopathy. Cleavage of ER-bound TREX1 by SPP releases a cleavage product into the cytosol. Proteolysis depends on sequence determinants within the transmembrane segment and is modulated by different disease-associated TREX1 variants. The AGS-causing T303P variant greatly enhanced susceptibility of TREX1 to intramembrane cleavage accounting for increased degradation and reduced protein stability in AGS patients homozygous for this variant. Other variants within the TREX1 transmembrane segment, P290L, Y305C and G306A, associated with systemic lupus erythematosus variably modulated TREX1 proteolytic processing. Altogether, intramembrane proteolysis can act as a regulator of TREX1 both by controlling its cytosolic localization and mediating its turnover with implications for disease pathogenesis.
Keywords
Exodeoxyribonucleases, Humans, Phosphoproteins, Nervous System Malformations, Proteolysis, Autoimmune Diseases of the Nervous System, HEK293 Cells, Membrane Proteins, Substrate Specificity, Lupus Erythematosus, Systemic
Published Open-Access
yes
Recommended Citation
Tever, Onur Kerem; Mentrup, Torben; Chinn, Ivan Kingyue; et al., "The DNase TREX1 Is a Substrate of the Intramembrane Protease Spp With Implications for Disease Pathogenesis" (2025). Faculty, Staff and Students Publications. 7649.
https://digitalcommons.library.tmc.edu/baylor_docs/7649