Abstract
γ-secretase and signal peptide peptidase (SPP) are unusual GxGD aspartyl proteases, which mediate intramembrane proteolysis. In addition to SPP, a family of SPP-like proteins (SPPLs) of unknown function has been identified. We demonstrate that SPPL2b utilizes multiple intramembrane cleavages to liberate the intracellular domain of tumor necrosis factor α (TNFα) into the cytosol and the carboxy-terminal counterpart into the extracellular space. These findings suggest common principles for regulated intramembrane proteolysis by GxGD aspartyl proteases.
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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB 596), the Gottfried Wilhelm Leibniz Award to C.H., the APOPIS Program (Abnormal proteins in the pathogenesis of neurodegenerative disorders - An integrated project funded by the EU under the SIXTH FRAMEWORK PROGRAMME; to C.H. and B.M.), National Genome Research Network 2 (NGFN-2) to C.H. and National Institute of Health (NIH, Bethesda, MD) grants NS38328, NS4414, and AG18921 to D.B.T. We thank S. Lichtenthaler and P.-H. Kuhn for providing TNFα cDNA and for helpful discussion.
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Fluhrer, R., Grammer, G., Israel, L. et al. A γ-secretase-like intramembrane cleavage of TNFα by the GxGD aspartyl protease SPPL2b. Nat Cell Biol 8, 894–896 (2006). https://doi.org/10.1038/ncb1450
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DOI: https://doi.org/10.1038/ncb1450
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