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@ARTICLE{Tever:299788,
      author       = {O. K. Tever and T. Mentrup and I. K. Chinn and H. Ishikuma
                      and R. Fluhrer and M. Schmitz and R. Wehner$^*$ and R.
                      Behrendt and J. Chinen and B. Schröder},
      title        = {{T}he {DN}ase {TREX}1 is a substrate of the intramembrane
                      protease {SPP} with implications for disease pathogenesis.},
      journal      = {Cellular and molecular life sciences},
      volume       = {82},
      number       = {1},
      issn         = {1420-682X},
      address      = {Cham (ZG)},
      publisher    = {Springer International Publishing AG},
      reportid     = {DKFZ-2025-00543},
      pages        = {107},
      year         = {2025},
      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: metabolism / Exodeoxyribonucleases:
                      genetics / Exodeoxyribonucleases: chemistry / Humans /
                      Phosphoproteins: metabolism / Phosphoproteins: genetics /
                      Autoimmune Diseases of the Nervous System: genetics /
                      Autoimmune Diseases of the Nervous System: metabolism /
                      Autoimmune Diseases of the Nervous System: pathology /
                      Nervous System Malformations: genetics / Nervous System
                      Malformations: metabolism / Nervous System Malformations:
                      pathology / Proteolysis / Membrane Proteins: metabolism /
                      Membrane Proteins: genetics / HEK293 Cells / Aspartic Acid
                      Endopeptidases: metabolism / Aspartic Acid Endopeptidases:
                      genetics / Lupus Erythematosus, Systemic: metabolism / Lupus
                      Erythematosus, Systemic: genetics / Lupus Erythematosus,
                      Systemic: pathology / Endoplasmic Reticulum: metabolism /
                      Nucleotidyltransferases / Aicardi-Goutières syndrome
                      (Other) / Cytosolic DNA degradation (Other) / ER-associated
                      protein degradation (Other) / Intramembrane proteolysis
                      (Other) / Signal peptide peptidase (Other) / cGAS/STING
                      pathway (Other) / three prime repair exonuclease 1 (NLM
                      Chemicals) / Exodeoxyribonucleases (NLM Chemicals) /
                      Phosphoproteins (NLM Chemicals) / Membrane Proteins (NLM
                      Chemicals) / Aspartic Acid Endopeptidases (NLM Chemicals) /
                      STING1 protein, human (NLM Chemicals) / cGAS protein, human
                      (NLM Chemicals) / Nucleotidyltransferases (NLM Chemicals)},
      cin          = {DD01},
      ddc          = {610},
      cid          = {I:(DE-He78)DD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40072623},
      doi          = {10.1007/s00018-025-05645-5},
      url          = {https://inrepo02.dkfz.de/record/299788},
}